Tranexamic acid formulations

ABSTRACT

Disclosed are modified release oral tranexamic acid formulations and methods of treatment therewith.

This application is a continuation of U.S. patent application Ser. No.13/230,902, filed Sep. 13, 2011, which is pending, which is acontinuation of U.S. patent application Ser. No. 12/433,510 filed Apr.30, 2009, now U.S. Pat. No. 8,022,106, which is a continuation-in-partof U.S. patent application Ser. No. 12/228,489, filed Aug. 13, 2008, nowU.S. Pat. No. 8,273,795, which is a continuation of U.S. patentapplication Ser. No. 11/072,194 filed Mar. 4, 2005, now abandoned, whichclaims the benefit of U.S. Provisional Application No. 60/550,113, filedMar. 4, 2004, and U.S. Provisional Application No. 60/592,885, filedJul. 30, 2004. The disclosures of these prior applications are herebyincorporated by reference in their entireties.

FIELD OF THE INVENTION

The invention is directed to modified release oral tranexamic acidformulations that preferably minimize or eliminate undesirable sideeffects and methods of treatment with these formulations.

BACKGROUND OF THE INVENTION

Tranexamic acid (trans-4-(aminomethyl) cyclohexanecarboxylic acid,Cyklokapron® (Pfizer) is an antifibrinolytic agent. That is, it helps toprevent lysis or dissolution of a fibrin clot which forms in the normalphysiologic process of hemostasis. Its mechanism of action is as acompetitive inhibitor of plasminogen activation, and as a noncompetitiveinhibitor of plasmin; both plasminogen and plasmin are activators offibrinolysis and active clot-lysing agents. Tranexamic acid thus helpsto stabilize fibrin clots, which in turn maintains coagulation and helpsto control bleeding.

Tranexamic acid is used to control excess bleeding, for example, excessbleeding that occurs during dental procedures in hemophiliacs and forheavy bleeding during menstruation (menorrhagia). Women suffering frommenorrhagia are typically treated orally with 500 mg tranexamic acidtablets administered three or four times daily with a total daily doseranging from 3 grams/day (two tablets every eight hours) to 6 grams/day(three tablets every six hours). However, this treatment may causeadverse gastrointestinal reactions, including nausea, vomiting,diarrhea, and cramping, etc. These gastrointestinal side effects are dueto the quantity of tranexamic acid and/or rapid rate of release oftranexamic acid into the stomach with each dose, as well as the largequantity of excipients used in the tablet formulation that areintroduced into the stomach. Such side effects, in addition to thecramping, bloating, pain, and other symptoms that may accompany menses,are undesirable, and a formulation of tranexamic acid is needed whichwill reduce or eliminate these side effects.

Menstrual Bleeding

Menstrual Bleeding disorders encompass a number of conditions includingbleeding associated with uterine fibroids, endometriosis, or bleeding asa result of deficiencies in the clotting process for example,von-Willebrand's disease. Studies suggest that as many as 11% of thewomen who experience heavy menstrual bleeding, suffer from an inheritedbleeding disorder such as von Willebrand's disease. Excessive MenstrualBleeding is menstruation at relatively regular intervals but withexcessive blood loss over the menses period which may be prolonged.Heavy Menstrual Bleeding (also referred to as “Menorrhagia”) is aserious, persistent, and recurrent medical condition that is one of themost common complaints encountered by gynecologists and primary carephysicians (Palep-Singh, 2007). A 2005 survey of 273obstetrician/gynecologists found that they see an average of 18 to 25symptomatic patients per month. Heavy Menstrual Bleeding is ahyperfibrinolytic condition defined as cyclic, normal intervals ofmenstruation with excessive volume. Menorrhagia is often associated witha disruption in daily routines, work, and sexual activity leading to asignificant decrease in health-related quality of life and time lostfrom work or school. While Menorrhagia is rarely life threatening, whenundiagnosed and untreated, it may over time cause iron deficiency anemiaand increased fatigue, both of which affect normal life activities,relationships, social activities, and various aspects of mentalwell-being (irritation, anxiety). Left untreated it may be associatedwith subsequent morbidity including dysmenorrhea, hospitalization, redblood cell transfusions and chronic pain. Annually, approximately 10% ofwomen of reproductive age report Menorrhagia (Rees 1991; van Eijkeren,1992) and according to the Center for Disease Control (CDC), 3 millionwomen of reproductive age report Menorrhagia yearly, 60% of which haveno known etiology. Studies report that as many as thirty percent ofpremenopausal women perceive their menses to be excessive.

Women suffering from menorrhagia often have greater uterine fibrinolyticactivity than women with normal cyclic menstrual blood loss (MBL). Highconcentrations of plasminogen activators are found in both the uterusand menstrual fluid (Albrechtsen, 1956a,b). Rybo (1966) foundsignificantly higher concentration of endometrial plasminogen activatorsin women with excessive menstrual bleeding compared to women with normalmenstrual loss.

Causes of Menorrhagia include pelvic diseases (myomata [fibroids],adenomyosis or uterine polyps), intrauterine contraceptive devices, andsystemic disorders (coagulopathies such as thrombocytopenia or vonWillebrand's disease, and hypothyroidism). In contrast to menorrhagia,the term ‘dysfunctional uterine bleeding’ refers to excessive, prolongedor irregular bleeding from the endometrium that is unrelated to systemicdisease (Wathen, 1995), and is usually associated with anovulation.Menorrhagia is also distinguished from other ovulatory bleedingdisorders, such as metrorrhagia (intermenstrual bleeding),menometrorrhagia (irregular heavy menstrual bleeding) and polymenorrhea(menstrual cycle less than 21 days).

Diagnosis of Menstrual Blood Loss

In clinical trials, menstrual blood loss (MBL) is usually determined bymeasuring the amount of hemoglobin recovered from sanitary productsduring the menstrual cycle, using the alkaline hematin method (Fraser,1994). However, it is important to remember that blood accounts for onlyabout 50% of total menstrual flow, with endometrial transudateaccounting for the remainder (Fraser, 1994). Total menstrual flow can beestimated by weighing of sanitary products or by comparisons with apictorial blood loss assessment chart. However, the use of thesequantitative and semi-quantitative methods is not practical in non-trialsettings. Rather, the diagnosis of Menorrhagia in the healthcare clinicis made by medical providers on the basis of patient's perceived andself-reported medical history, routine laboratory assessments of thepatient's general health status, and gynecological examinations.

Clinically heavy menstrual bleeding is sometimes defined as total bloodloss exceeding about 80 ml per cycle or menses lasting longer than sevendays. The volume lost however, varies widely. Clinically losses fromabout 30 ml to 60 ml, 60 to 80 ml, 80 to 100 ml, to as high as 1000 mlper cycle are observed. Menstrual blood losses of 50 to 60 ml areassociated with a negative iron balance and iron deficiency anemia isdiagnosed in about 67% of the women who lose an excess of 80 ml per day.Other criteria for diagnosing the condition include measuring the numberand size of blood clots in the meneges, or monitoring the use of pads ortampons. It is estimated that perhaps only ten percent of women whoperceive their loss to be excessive actually fall within the clinicaldefinition. The 80 ml definition has been repeatedly questioned, andalternative definitions broadened the blood loss range used for patientevaluations.

Blood loss volume assessments commonly require the collection andpreservation of menstrual pads or tampons, the extraction of the padsand the accurate measurement of the blood content. Women are instructedto collect all sanitary towels and tampons during the course of themenstrual diagnosis period or the course of a clinical study period.Blood loss can be measured by extraction of the blood from the sanitarymaterial with 5% sodium hydroxide followed with a spectrophotometricmeasurement of hematin at a wavelength of about 540 nm. The total bloodloss can be calculated for an individual by comparison of the patient'splasma blood hemoglobin measurement with the collected hemoglobinvalues.

The collection of the blood sample discourages the routine use of thetest in the diagnosis or in the treatment of the condition. In thecourse of a routine visit with a physician other blood work may beappropriate but lacks a casual relation to the heavy bleeding disorder.The battery of routine laboratory tests may include patient bloodhemoglobin, haematocrit, platelet count, bilirubin, serum creatinine andserum ferritin. In sum, diagnosis in the routine course of practicerelies heavily on the woman's perception of the volume of blood lostduring menses.

Diagnosis and Treatment of Heavy Menstrual Bleeding Disorders(Menorrhagia)

A number of medical and surgical interventions are available to treatmenstrual bleeding disorders. Currently available non-surgicaltreatments for heavy bleeding disorders, include, hormonal treatments(e.g., oral contraceptives), high-dose progestin therapy, desmopressinacetate, ethamsylate, nonsteroidal anti-inflammatory drugs (NSAIDs), theantifibrinolytic drugs aminocaproic acid and tranexamic acid. Even withthe drug treatments available, surgery remains a common treatment.

Although not approved for menorrhagia in the US, use of oralcontraceptives for menorrhagia is widely accepted. Oral contraceptivesmay not be a preferred therapy for some women because of age (youngerfemales), unwanted side effects (nausea and vomiting, breakthroughbleeding, weight change, migraines and depression), and safety concerns(increased risk of thromboembolism, stroke, myocardial infarction,hepatic neoplasia and gall bladder disease). High-dose progestin(synthetic versions of the hormone progesterone) may also be given towomen with menorrhagia, either orally or by a progestin-releasing deviceinserted into the uterus (intrauterine device). Side effects includenausea, bloating, mood changes, and breast tenderness.

Although it is typically a last resort, desmopressin acetate issometimes used to help lighten menstrual flow in women with menorrhagia.The effectiveness of desmopressin is thought to vary betweenindividuals. Side effects include headache, tachycardia, facialflushing, and rare reports of thromboembolism.

NSAIDs are sometimes used to treat menorrhagia as they may reduce bloodflow while providing analgesia for pain associated with the condition(Shaw, 1994). Side effects associated with chronic NSAID use includegastrointestinal bleeding, ulceration, and perforation; and renaleffects such as hyperkalemia, hyponatremia, acute renal insufficiency,interstitial nephritis, and renal papillary necrosis.

Hysterectomy or endometrial resection are options if other forms oftherapy are not effective or are unsuitable for some reason. Possiblesurgical complications include infection, uterine perforation, and othercomplications associated with major surgery.

Antifibrinolytic drugs, such as ε-aminocaproic acid and tranexamic acid(immediate-release formulation) have been used to treat HMB in womenwith or without a diagnosed bleeding disorder (van Eijkeren, 1992;Bonnar, 1996; Vermylen, 1968; Nilsson, 1965). The available evidencefrom published literature suggests that tranexamic acid at doses of ˜4g/day (typically 1 g every 6 hours) is effective in the treatment of HMBand is associated with few side effects (Callender, 1970; Dunn, 1999;Edlund, 1995; Preston, 1995). In Sweden, the average dose of tranexamicacid to treat HMB is 3.9 g/day (Rybo, 1991). Thus, tranexamic acid isused extensively in Europe, Canada, Asia, Japan, Australia and NewZealand to treat menorrhagia, but is not approved for this indication inthe US.

Tranexamic acid is a competitive inhibitor of plasminogen activation(see review by Dunn, 1999). Binding of tranexamic acid to plasminogendoes not prevent conversion of plasminogen to plasmin by tissueplasminogen activator, but the resulting plasmin/tranexamic acid complexis unable to bind to fibrin. Thus, enzymatic breakdown of fibrin byplasmin (fibrinolysis) is inhibited. At higher concentrations,tranexamic acid is also a noncompetitive inhibitor of plasmin.

Before medical and surgical interventions can be initiated, diagnosis ofa heavy menstrual bleeding disorder must be accomplished.

Diagnosis and treatment of disease often depends on the patient'sperception and subsequent description of symptoms, the physician'sevaluation of the patient's description, the physician observations ofthe patient and laboratory test results. Menstrual bleeding disorders donot lend themselves to physician observation or to routine laboratorytesting. Patient observations and the physician's evaluation of thepatient's description are subjective and thus variable. In addition awomen's medical history has been found to be a poor predictor ofmenstrual blood loss. Neither the duration of menses nor the number ofsanitary pads worn accurately corresponds to the woman's actualmenstrual blood loss (Chimbira, Haynes, year). An objective assessmentof blood loss using the alkaline haematin assay has been shown to bereproducible but it is not suited for routine clinical use by healthcareproviders. To date no effective instrument for reliably diagnosingand/or monitoring the treatment of menstrual bleeding disorders has beendeveloped despite the significant number of women who suffer from theseconditions.

Previously, studies have focused on the impact of symptoms of bleedingdisorders on patients' health related quality of life. As the effects ofmenstrual bleeding disorders are primarily symptomatic, the subjectiveoutcome namely symptom alleviation, cannot be objectively measured. Inresearch from European countries where the antifibrinolytic drugtranexamic acid is currently available, treatment with thisantifibrinolytic has reduced heavy menstrual bleeding by 40-50% andimproved the health-related quality of life of affected women onmeasures of social activity, work performance, productivity,cleanliness, overall functioning and tiredness.

Jenkinson et al, Quality in Health Care 1996; 5; 9-12 evaluated thevalidity and internal reliability of the short form-36 (SF36) healthsurvey questionnaire in women presenting with menorrhagia. The studyconcluded that several questions on the questionnaire were difficult toanswer for patients with heavy menstrual bleeding. Such problems weresuggested as possible interferences with the validity of the measure.Jenkinson warns that because a subjective measure works well in onepopulation or with one group, this cannot be taken to imply itsappropriateness for all groups or conditions.

Edlund, in an abstract from a seminar on Dysfunctional Uterine Bleeding,Feb. 23, 1994, indicates that a questionnaire was used in a Swedishstudy of 2205 women who described their menstruation as excessive.

Winkler in a study based in part on the Edlund work, concluded that thetreatment of heavy menstrual bleeding with tranexamic acid increased thequality of life of the treated patients. The Winkler study was an openlabel uncontrolled usage study which included 849 patients. Aquestionnaire was used prior to treatment and after the first and thirdmenstruation. The study indicates that 80% of the women were satisfiedwith the treatment. The questionnaire used a series of eight questioncombined with an assessment by the patients of the change in quantity ofmenstrual flow.

Ruta, D. A., Quality of Life Research, 4, (33-40), 1995 finds thatmenorrhagia is a common problem in gynecological practice and that womenseek professional help primarily because of the deleterious effect ontheir quality of life. Ruta recognizing the importance of evaluating theeffectiveness of the treatments developed a questionnaire based on thetype of questions frequently asked when taking a gynecological history.A series of questions were devised which assessed fifteen factorsincluding the duration of the period, the regularity of the period,pain, problems with soiling/staining, interference with work,interference with leisure. Ruta concluded that the clinicalquestionnaire may be useful in selecting patients for hysterectomy andassessing the outcome of conservative treatment especially incombination with the SF-36 questionnaire.

Diagnostic Test for Menstrual Bleeding

The alkaline haematine test described above provides quantitativeassessments of the extent of menstrual bleeding. This test allows thephysician to diagnose and monitor the progress of a women's menstrualprocess. However the test is impractical and difficult to perform. Thetest requires women to capture used menstrual pads over the course ofher period, preserve the samples in a condition such that the bloodcontent within the pad may be accurately extracted and quantitated.Requesting a patient to perform menses sample collection may bepractical in the course of a clinical trial where procedures arespecified and monitored however, in routine medical practice, the use ofsuch a test procedure to diagnose and monitor a women's menstrualbleeding is impractical and the data generated is unreliable.

The need remains to develop an assessment system which replacespreviously studied diagnostic techniques and the alkaline haematine testand provides a reliable measure of both the occurrence of the disorderand the progress of the disorder. The present invention fills this needby providing a Heavy Menstrual Bleeding Instrument (HMBI) which iscapable of diagnosing, and monitoring the treatment of a patient with amenstrual bleeding disorder.

There also remains a need to provide Heavy Menstrual Bleeding (HMB)therapy that is safe, efficacious and only administered during themonthly period of heavy menstruation, addresses the excessivefibrinolysis implicated in many causes of menorrhagia, and fills acurrently recognized unmet medical need in the US. Therapy for HMB isexpected to reduce the incidence and extent of iron-deficiency anemia,and to provide a nonhormonal medical therapy option in lieu of thenumerous invasive procedures (e.g., transcervical endometrial resection)and major surgery (hysterectomy) performed annually.

SUMMARY OF THE INVENTION

Formulations of tranexamic acid which minimize or eliminate theundesirable gastrointestinal side effects in patients on oral tranexamicacid therapy, e.g. women treated for menorrhagia (heavy menstrualbleeding) are disclosed. The present invention is directed in part to amodified release formulation, formulated so that the release oftranexamic acid thereof from the dosage form occurs in a designedfashion to prevent a bolus of tranexamic acid being introduced into thestomach and available for dissolution in the gastric contents. Suchmodified release formulations reduce the concentration of tranexamicacid dissolved in the stomach contents such as e.g., preventing a largebolus of tranexamic acid being introduced in the stomach. The beneficialeffect of this reduced tranexamic acid concentration is to lower theamount of tranexamic acid in the gastric contents so that there arefewer adverse effects with tranexamic acid therapy. This reduction inadverse effects preferably results in improved patient compliance withtherapy, because preferably patients will not intentionally miss takinga dose to avoid these adverse side effects. Physicians will alsopreferably be more likely to initiate and maintain tranexamic acidtreatment for their patients because of the reduced patient complaints.

It is an object of the invention to provide an oral dosage formcomprising tranexamic acid which is suitable for administration on a twoor three times a day basis to humans.

It is a further object of the invention to provide a modified releaseoral dosage form comprising tranexamic acid and a modified releasematerial which provides for the modified release of the tranexamic acidand is suitable for administration on a two or three times a day basis.

It is a further object of certain embodiments of the present inventionto provide a modified release oral dosage form comprising tranexamicacid and a modified release material which minimizes or eliminates theundesirable gastrointestinal side effects in patients on oral tranexamicacid therapy while maintaining or improving the therapeutic effect oftranexamic acid.

It is a further object of certain embodiments of the present inventionto provide a method of treating a patient suffering from heavy menstrualbleeding (menorrhagia) by orally administering to the patient one ormore dosage forms comprising tranexamic acid and a modified releasematerial which provide(s) for therapeutically effective levels oftranexamic acid suitable for two or three times a day administration.

The above advantages and objects and others can be achieved by virtue ofthe present invention which is directed in part to a modified releaseoral dosage form comprising tranexamic acid or a pharmaceuticallyacceptable salt thereof and a modified release material which providesfor the modified release of the tranexamic acid or pharmaceuticallyacceptable salt thereof from the dosage form such that the dosage formis suitable for administration on a two or three times a day basis; saiddosage form providing an in-vitro dissolution release rate of thetranexamic acid or pharmaceutically acceptable salt thereof, whenmeasured by a USP 27 Apparatus Type II Paddle Method @ 50 RPM in 900 mlwater at 37±0.5° C., of less than about 70% by weight tranexamic acid orpharmaceutically acceptable salt thereof released at about 45 minutesand about 100% by weight of said tranexamic acid or pharmaceuticallyacceptable salt thereof released by about 120 minutes.

In certain embodiments, the present invention is directed to a method oftreating a patient in need of tranexamic acid or pharmaceuticallyacceptable salt thereof therapy comprising administering to the patientabout 1300 mg of tranexamic acid or pharmaceutically acceptable saltthereof in at least one oral dosage form comprising said tranexamic acidor pharmaceutically acceptable salt thereof and a modified releasematerial which provides a mean maximum plasma concentration (C_(max)) oftranexamic acid of from about 5 to about 17.5 mcg/ml, preferably fromabout 6.5 to about 15 mcg/ml, more preferably from about 9 to about 14.5mcg/ml after single dose oral administration to humans.

In certain embodiments, the invention is further directed to a method oftreating a patient in need of tranexamic acid or pharmaceuticallyacceptable salt thereof therapy comprising administering to the patientabout 1300 mg of tranexamic acid or pharmaceutically acceptable saltthereof in at least one oral dosage form comprising said tranexamic acidor pharmaceutically acceptable salt thereof and a modified releasematerial which provides a mean maximum plasma concentration (C_(max)) oftranexamic acid of from about 5 to about 25 mcg/ml, preferably fromabout 10 to about 20 mcg/ml, more preferably from about 12.5 to about17.5 mcg/ml, most preferably about 15 to about 17 mcg/ml after steadystate oral administration to humans.

In certain embodiments, the modified release oral dosage form of thepresent invention provides a mean T_(max) of tranexamic acid at fromabout 1 to about 5.5 hours, preferably at from about 2 to about 4 hours,more preferably at from about 2 to about 3.5 hours after oraladministration of the dosage form to humans.

In certain embodiments, the invention is further directed to a modifiedrelease oral dosage form comprising tranexamic acid or pharmaceuticallyacceptable salt thereof and a modified release material which providesfor the modified release of the tranexamic acid or pharmaceuticallyacceptable salt thereof from the dosage form such that the dosage formis suitable for administration on a two or three times a day basis andthe dosage form provides a dissolution release rate in-vitro of thetranexamic acid or pharmaceutically acceptable salt thereof whenmeasured by the USP 27 Apparatus Type II Paddle Method @ 50 RPM in 900ml water at 37±0.5° C. of less than about 40% by weight tranexamic acidor pharmaceutically acceptable salt thereof released at about 15minutes, less than about 70% by weight tranexamic acid orpharmaceutically acceptable salt thereof released at about 45 minutes,and not less than 50% by weight tranexamic acid or pharmaceuticallyacceptable salt thereof released at about 90 minutes.

In certain embodiments, the invention is further directed to a modifiedrelease oral dosage form comprising tranexamic acid or pharmaceuticallyacceptable salt thereof and a modified release material which providesfor the modified release of the tranexamic acid or pharmaceuticallyacceptable salt thereof from the dosage form such that the dosage formis suitable for administration on a two or three times a day basis andthe dosage form provides a dissolution release rate in-vitro of thetranexamic acid or pharmaceutically acceptable salt thereof whenmeasured by the USP 27 Apparatus Type II Paddle Method @ 50 RPM in 900ml water at 37±0.5° C. of about 0% to about 40% by weight tranexamicacid or pharmaceutically acceptable salt thereof released at about 15minutes, from about 20% to about 60% by weight tranexamic acid orpharmaceutically acceptable salt thereof released at about 30 minutes,from about 40% to about 65% by weight tranexamic acid orpharmaceutically acceptable salt thereof released at about 45 minutes,from about 50% to about 90% by weight tranexamic acid orpharmaceutically acceptable salt thereof release at about 60 minutes,and not less than 60% by weight tranexamic acid or pharmaceuticallyacceptable salt thereof released at about 90 minutes.

In certain embodiments, the invention is further directed to a modifiedrelease oral dosage form comprising tranexamic acid or pharmaceuticallyacceptable salt thereof and a modified release material, which providesfor a bioavailability of tranexamic acid of greater than 40%, from about41% to about 60%, preferably from about 42% to about 50%, morepreferably about 45% after oral administration to humans.

In certain embodiments, the present invention is further directed to amodified release oral dosage form comprising from about 585 to about 715mg of tranexamic acid or pharmaceutically acceptable salt thereof,preferably about 650 mg of tranexamic acid or pharmaceuticallyacceptable salt thereof, and a modified release material which providesfor the modified release of the tranexamic acid or pharmaceuticallyacceptable salt thereof from the dosage form such that the dosage formis suitable for administration on a two or three times a day basis.

In certain embodiments, the present invention is directed to a modifiedrelease oral dosage form comprising tranexamic acid or pharmaceuticallyacceptable salt thereof and a modified release material which providesfor the modified release of the tranexamic acid or pharmaceuticallyacceptable salt thereof from the dosage form such that the dosage formis suitable for administration on a two or three times a day basis, thedosage form providing a reduction of at least one side effect selectedfrom the group consisting of headache, nausea, vomiting, diarrhea,constipation, cramping, bloating, and combinations thereof, as comparedto an equivalent amount of tranexamic acid or pharmaceuticallyacceptable salt thereof in an immediate release oral dosage form whenadministered across a patient population.

In certain embodiments, the present invention is directed to a modifiedrelease oral dosage form comprising tranexamic acid or pharmaceuticallyacceptable salt thereof and a modified release excipient, said dosageform providing for the release of the tranexamic acid orpharmaceutically acceptable salt thereof which is slower than animmediate release oral dosage form and faster than a controlled releaseoral dosage form, such that the modified release oral dosage form issuitable for administration two or three times a day.

In certain embodiments, the invention is further directed to a modifiedrelease oral dosage form comprising about 650 mg of tranexamic acid orpharmaceutically acceptable salt thereof and a modified releasematerial, the dosage form being suitable for oral administration on athree times a day basis, and the dosage form providing a mean maximumplasma concentration (C_(max)) of tranexamic acid of from about 5 toabout 17.5 mcg/ml, preferably from about 6.5 to about 15 mcg/ml, morepreferably from about 9 to about 14.5 mcg/ml per 1300 mg tranexamic acidafter single dose oral administration to humans.

In certain embodiments, the invention is further directed to a modifiedrelease oral dosage form comprising about 650 mg of tranexamic acid orpharmaceutically acceptable salt thereof and a modified releasematerial, the dosage form being suitable for oral administration on atwice a day basis, and the dosage form providing a mean maximum plasmaconcentration (C_(max)) of tranexamic acid of from about 5 to about 40mcg/ml, preferably from about 10 to about 30 mcg/ml per 1950 mgtranexamic acid after single dose oral administration to humans.

In certain embodiments, the invention is further directed to a modifiedrelease oral dosage form comprising about 650 mg of tranexamic acid orpharmaceutically acceptable salt thereof and a modified releasematerial, the dosage form being suitable for oral administration on athree times a day basis, and the dosage form providing a mean plasmaconcentration of tranexamic acid of from about 5 to about 25 mcg/ml,preferably from about 7.5 to about 15 mcg/ml, more preferably from about8 to about 10 mcg/ml, most preferably about 9 mcg/ml per 1300 mgtranexamic acid after steady state oral administration to humans.

In certain embodiments, the invention is further directed to a modifiedrelease oral dosage form comprising about 650 mg of tranexamic acid orpharmaceutically acceptable salt thereof and a modified releasematerial, the dosage form being suitable for administration on a threetimes a day basis, and the dosage form providing a mean maximum plasmaconcentration (C_(max)) of tranexamic acid of from about 5 to about 25mcg/ml, preferably from about 10 to about 20 mcg/ml, more preferablyfrom about 12.5 to about 17.5 mcg/ml, most preferably about 15 to about17 mcg/ml per 1300 mg tranexamic acid after steady state oraladministration to humans.

In certain embodiments, the invention is further directed to a modifiedrelease oral dosage form comprising about 650 mg of tranexamic acid orpharmaceutically acceptable salt thereof and an modified releasematerial, the dosage form being suitable for administration on a threetimes a day basis, and the dosage form providing a mean plasma troughconcentration of tranexamic acid or pharmaceutically acceptable saltthereof of from about 2 to about 10 mcg/ml, preferably from about 3 toabout 7.5 mcg/ml, more preferably about 4 to about 7 mcg/ml, mostpreferably about 5 to about 6 mcg/ml per 1300 mg tranexamic acid orafter steady state oral administration to humans.

In certain embodiments, the invention is further directed to a method oftreating a patient with a therapeutically effective amount of tranexamicacid or pharmaceutically acceptable salt thereof comprisingadministering to the patient two dosage forms of the present invention,each dosage form comprising from about 585 mg to about 715 mg oftranexamic acid or pharmaceutically acceptable salt thereof, preferablyabout 650 mg tranexamic acid or pharmaceutically acceptable saltthereof, and a modified release material such that the dosage form issuitable for oral administration on a three times a day basis.

In certain embodiments, the invention is further directed to a method oftreating a patient with a therapeutically effective amount of tranexamicacid or pharmaceutically acceptable salt thereof comprisingadministering to the patient three dosage forms of the presentinvention, each dosage form comprising from about 585 mg to about 715mg, preferably about 650 mg tranexamic acid or pharmaceuticallyacceptable salt thereof, and a modified release material such that thedosage form is suitable for oral administration on a twice a day basis.

In certain embodiments, the invention is directed to a dose oftranexamic acid or pharmaceutically acceptable salt thereof comprisingtwo unit dosage forms of a modified release formulation, each unitdosage form of said modified release formulation comprising from about585 mg to about 715 mg, preferably about 650 mg of tranexamic acid orpharmaceutically acceptable salt thereof, and a modified releasematerial which provides for the release of the tranexamic acid orpharmaceutically acceptable salt thereof from the dosage form such thatthe dose provides a therapeutic effect when administered three times aday.

In certain embodiments, the invention is directed to a dose oftranexamic acid comprising three unit dosage forms of a modified releaseformulation, each unit dosage form of said modified release formulationcomprising from about 585 mg to about 715 mg, preferably about 650 mg oftranexamic acid or pharmaceutically acceptable salt thereof, and amodified release material which provides for the release of thetranexamic acid or pharmaceutically acceptable salt thereof from thedosage form such that the dose provides a therapeutic effect whenadministered twice a day.

In certain preferred embodiments, the invention is further directed to amodified release oral dosage form including tranexamic acid orpharmaceutically acceptable salt thereof and a modified release materialwhich provides for the modified release of the tranexamic acid orpharmaceutically acceptable salt thereof from the dosage form such thatthe dosage form is suitable for administration on a two or three times aday basis and the dosage form provides a dissolution release ratein-vitro of the tranexamic acid or pharmaceutically acceptable saltthereof when measured by the USP 27 Apparatus Type II Paddle Method @ 50RPM in 900 ml water at 37±0.5° C. of about 0% to about 40% by weighttranexamic acid or pharmaceutically acceptable salt thereof released atabout 15 minutes, from about 20% to about 60% by weight tranexamic acidor pharmaceutically acceptable salt thereof released at about 30minutes, from about 40% to about 80% by weight tranexamic acid orpharmaceutically acceptable salt thereof released at about 45 minutes,from about 50% to about 95% by weight tranexamic acid orpharmaceutically acceptable salt thereof release at about 60 minutes,and not less than about 60% by weight tranexamic acid orpharmaceutically acceptable salt thereof released at about 90 minutes.

In certain preferred embodiments, the invention is further directed to amodified release oral dosage form including tranexamic acid orpharmaceutically acceptable salt thereof and a modified release materialwhich provides for the modified release of the tranexamic acid orpharmaceutically acceptable salt thereof from the dosage form such thatthe dosage form is suitable for administration on a two or three times aday basis and the dosage form provides a dissolution release ratein-vitro of the tranexamic acid or pharmaceutically acceptable saltthereof when measured by the USP 27 Apparatus Type II Paddle Method @ 50RPM in 900 ml water at 37±0.5° C. of about 14% to about 22% by weighttranexamic acid or pharmaceutically acceptable salt thereof released atabout 15 minutes, from about 32% to about 50% by weight tranexamic acidor pharmaceutically acceptable salt thereof released at about 30minutes, from about 47% to about 71% by weight tranexamic acid orpharmaceutically acceptable salt thereof released at about 45 minutes,from about 61% to about 92% by weight tranexamic acid orpharmaceutically acceptable salt thereof release at about 60 minutes,and from about 79% to about 100% by weight tranexamic acid orpharmaceutically acceptable salt thereof released at about 90 minutes.

In certain embodiments, the invention is directed to a modified releaseoral dosage form comprising tranexamic acid or pharmaceuticallyacceptable salt thereof and an effective amount of a modified releaseexcipient such that the dosage form releases from about 10% to about 25%by weight tranexamic acid or pharmaceutically acceptable salt thereofevery 15 minutes when measured in vitro utilizing the USP 27 ApparatusType II Paddle Method @ 50 RPM in 900 ml water at 37±0.5° C. In certainpreferred embodiments, the dosage form releases about 18% to about 23%by weight tranexamic acid or pharmaceutically acceptable salt thereofevery 15 minutes when measured in vitro utilizing the USP 27 ApparatusType II Paddle Method @ 50 RPM in 900 ml water at 37±0.5° C. Mostpreferably, the dosage form releases about 100% of said tranexamic acidor pharmaceutically acceptable salt thereof within about 120 minuteswhen measured in vitro utilizing the USP 27 Apparatus Type II PaddleMethod @ 50 RPM in 900 ml water at 37±0.5° C. In certain embodiments,the dosage form releases about 1% of said tranexamic acid orpharmaceutically acceptable salt thereof every minute when measured invitro utilizing the USP 27 Apparatus Type II Paddle Method @ 50 RPM in900 ml water at 37±0.5° C.

In certain preferred embodiments, the modified release oral dosage formof the invention further provides a mean transit time of said tranexamicacid of 7.70±0.72 hours when administered across a patient population.

In certain preferred embodiments, the modified release oral dosage formof the invention further provides a mean absorption time of saidtranexamic acid of 4.18±0.70 hours when administered across a patientpopulation.

In certain further embodiments, the modified release oral dosage form ofthe present invention provides confidence intervals derived fromln-transformed pharmacokinetic kinetic parameters AUC_(0-t), AUC_(inf)and C_(max) for tranexamic acid in plasma which are within a 80-125%range of an immediate release formulation including an equivalent amountof tranexamic acid when administered across a patient population underfasted conditions.

In certain embodiments, the invention is further directed to a modifiedrelease oral dosage form comprising tranexamic acid or pharmaceuticallyacceptable salt thereof and a modified release material which providesfor the modified release of the tranexamic acid or pharmaceuticallyacceptable salt thereof from the dosage form such that the dosage formis suitable for administration on a two or three times a day basis andthe dosage form provides less than about 20 percent incidence ofheadache as a side effect after single dose oral administration across apatient population.

In certain embodiments, the invention is further directed to a modifiedrelease oral dosage form comprising tranexamic acid or pharmaceuticallyacceptable salt thereof and a modified release material which providesfor the modified release of the tranexamic acid or pharmaceuticallyacceptable salt thereof from the dosage form such that the dosage formis suitable for administration on a two or three times a day basis andthe dosage form provides less than about 10 percent incidence of nauseaas a side effect when administered across a patient population, lessthan about 7 percent incidence of nausea when administered across apatient population, preferable less than about 5 percent incidence ofnausea as a side effect when administered across a patient population,more preferably less than about 2 percent incidence of nausea as a sideeffect after single dose oral administration across a patientpopulation.

In certain embodiments, the modified release oral dosage form of thepresent invention provides less CNS side effects (e.g., headache), lessGI side effects (e.g., nausea), or combination thereof in comparison toan equivalent amount of tranexamic acid or pharmaceutically acceptablesalt thereof in an immediate release formulation when administeredacross a patient population. Additionally or alternatively, in certainembodiments the dosage form provides less CNS side effects (e.g.,headache), less GI side effects (e.g., nausea), or combination thereofin comparison to a therapeutically equivalent amount of tranexamic acidadministered intravenously in five minutes or less across a patientpopulation.

In certain embodiments, the modified release oral dosage form of thepresent invention provides for the reduction of at least one side effectas compared to an immediate release oral dosage form including anequivalent amount of tranexamic acid or pharmaceutically acceptable saltthereof, when the immediate release dosage form is administered across asame or different population of patients as said modified release dosageform, and wherein said immediate release dosage form releases all ofsaid tranexamic acid or pharmaceutically acceptable salt thereof withinabout 45 minutes when measured in vitro utilizing the USP 27 ApparatusType II Paddle Method @ 50 RPM in 900 ml water at 37±0.5° C. Such sideeffects can be for example, headache, nausea, vomiting, diarrhea,constipation, cramping, bloating, and combinations thereof.

In certain embodiments, the modified release oral dosage form of thepresent invention provides a mean transit time of tranexamic acid whichis at least about 20 minutes longer, preferably about 30 minutes longer,than an immediate release formulation including an equivalent amount oftranexamic acid when administered across a patient population.

In certain embodiments, the dosage form of the present inventionprovides a mean absorption time of tranexamic acid which is at leastabout 20 minutes longer, preferably about 30 minutes longer, than animmediate release formulation including an equivalent amount oftranexamic acid when administered across a patient population.

In certain preferred embodiments, the therapeutically effective dose ofthe tranexamic acid or pharmaceutically acceptable salt thereof isprovided via the administration of two or more dosage units. Forexample, if the dosage unit comprises 650 mg of tranexamic acid orpharmaceutically acceptable salt thereof and the dose for administrationis about 1300 mg then two dosage units would be administered to apatient in need of such treatment, or for example, when the dose foradministration is 1950 mg, three dosage units would be administered.

In certain preferred embodiments, the invention is further directed to amethod of treating a patient with one or more modified release oraldosage forms comprising tranexamic acid or pharmaceutically acceptablesalt thereof and a modified release material, wherein the oral dosageform provides a therapeutically effective plasma level of tranexamicacid or pharmaceutically acceptable salt thereof in accordance with athree times a day (TID) dosing schedule, and the therapeuticallyeffective dose administered comprises about 1300 mg of tranexamic acidor pharmaceutically acceptable salt thereof.

In certain preferred embodiments, the invention is further directed to amethod of treating a patient with one or more modified release oraldosage forms comprising tranexamic acid or pharmaceutically acceptablesalt thereof and a modified release material, wherein the oral dosageform provides a therapeutically effective plasma level of tranexamicacid or pharmaceutically acceptable salt thereof in accordance with atwice a day (BID) dosing schedule, and the therapeutically effectivedose administered comprises about 1950 mg of tranexamic acid orpharmaceutically acceptable salt thereof.

In certain embodiments, the invention is directed to a method ofproviding a tranexamic acid plasma concentration within the range ofabout 5 mcg/mL to about 15 mcg/mL by administration of a modifiedrelease formulation of the present invention comprising tranexamic acidor pharmaceutically acceptable salt thereof and a modified releasematerial on a three times a day basis to a patient in need of tranexamicacid or pharmaceutically acceptable salt thereof treatment.

In certain embodiments, the invention is further directed to a method oftreating a human patient with heavy menstrual bleeding (e.g.,menorrhagia) comprising administering about 1300 mg of tranexamic acidor pharmaceutically acceptable salt thereof on a three times a day basisto the human patient to provide a tranexamic acid or pharmaceuticallyacceptable salt thereof plasma concentration within the range of about 5mcg/mL to about 15 mcg/mL after steady state oral administration to ahuman patient.

In certain embodiments, the invention is directed to a method oftreating a patient suffering from menorrhagia, including patients withheavy menstrual bleeding due to fibroids, conization of the cervix,epistaxis, hyphema, hereditary angioneurotic edema, a patient with ablood coagulation disorder undergoing dental surgery, combinationsthereof, and the like, by administering at least one dosage form of thepresent invention to the patient in need in tranexamic acid orpharmaceutically acceptable salt thereof therapy.

In certain embodiments, the invention is directed to a method oftreating heavy menstrual bleeding with a therapeutically effective doseof at least one oral formulation of the present invention comprisingtranexamic acid or pharmaceutically acceptable salt thereof and amodified release material wherein the menstrual blood loss per menstrualcycle is reduced by at least about 10 ml, preferably at least about 20ml, more preferably at least about 40 ml. In a most preferred embodimentthe menstrual blood loss per menstrual cycle is reduced by greater thanor equal to about 50 ml.

In certain embodiments, the invention is directed to a method oftreating heavy menstrual bleeding with a therapeutically effective doseof at least one oral formulation of the present invention comprisingtranexamic acid or pharmaceutically acceptable salt thereof and amodified release material which upon oral administration to a humanfemale reduces the blood loss per menstrual cycle by about 35 ml toabout 200 ml, preferably about 40 ml to about 175 ml, more preferablyfrom about 50 ml to about 150 ml.

In certain embodiments, the invention is further directed to a method oftreating heavy menstrual bleeding with a therapeutically effective doseof at least one oral formulation of the present invention comprisingtranexamic acid or pharmaceutically acceptable salt thereof and amodified release material which upon oral administration to a humanfemale reduces the blood loss per menstrual cycle by about 20% to 100%,preferably from about 20% to about 70%.

In certain other embodiments, the present invention is directed to theuse of the tranexamic acid formulations described herein for thetreatment of heavy menstrual bleeding (menorrhagia) and the ameliorationof symptoms associated with heavy menstrual bleeding, includinglimitations on social, leisure, and physical activities.

The menstrual blood loss can be measured by procedures known in the art.For example, in certain embodiments, the menstrual blood loss can bedetermined by a procedure described by (i) L. Hallbert, et al. in“Determination of Menstrual Blood Loss”, Scandinay. J. Clin. & Lab.Investigation, 244-248, 16, 1964, wherein the procedure is performed byextracting the menstrual blood from vaginal tampons and towels with asodium hydroxide solution, converting heme chromogens to alkalinehematin, which is determined spectrophotometrically; or (ii) themenstrual blood loss can be determined by a procedure described by J.Newton, M. D., et al., in “A Rapid Method for Measuring Menstrual BloodLoss Using Automatic Extraction.”, Contraception, 269-282, September1977, Vol. 16, No. 3, wherein the procedure is based upon the formationof alkaline haematin after the blood has been extracted from vaginaltampons and sanitary towels by an automatic Stomacher Lab-Blender. Thedisclosures of the aforementioned articles are hereby incorporated byreference in their entireties.

In certain embodiments, the modified release material may beincorporated in a coating applied onto e.g., a tablet comprising thetranexamic acid or pharmaceutically acceptable salt thereof, or may beincorporated into a matrix with the tranexamic acid or pharmaceuticallyacceptable salt thereof, or a combination thereof. For example, incertain preferred embodiments, the modified release material is acontrolled release material such as a gel-forming or hydratable polymerwhich is added to e.g., a matrix composition comprising the tranexamicacid or pharmaceutically acceptable salt thereof.

In certain embodiments, the tranexamic acid for use in the methods andformulations of the present invention is in the form of apharmaceutically acceptable salt thereof. Such salt forms include forexample and without limitation the sodium salt, potassium salt, calciumsalt, magnesium salt and the like; as well as the hydrochloride,hydrobromide, sulfate, phosphate, formate, acetate, trifluoroacetate,maleate, tartrate, methanesulfonate, benzenesulfonate,p-toluenesulfonatemethanesulfonate salt forms, and the like. Preferablythe active ingredient for use in accordance with the present inventionis tranexamic acid.

An “immediate release oral dosage form” for purposes of the presentinvention is a dosage form which releases all of active ingredient(e.g., tranexamic acid) included therein within about 45 minutes whenmeasured in vitro utilizing the USP 27 Apparatus Type II Paddle Method @50 RPM in 900 ml water at 37±0.5° C.

A “modified release oral dosage form” for purposes of the presentinvention is an oral dosage form which releases the active ingredient(e.g., tranexamic acid) included therein in a manner that is slower thanan immediate release oral dosage form and faster than a controlledrelease oral dosage form, when the dosage forms include the same amountof active as the modified release oral dosage form. One definition ofthe terms “slower” and “faster” as used in this application is that theyare meant to represent a statistically significant difference at eachmeasured 15 minute interval after the start of in-vitro dissolution. Incertain preferred embodiments, the modified release oral dosage form ofthe present invention provides an in-vitro dissolution release rate oftranexamic acid or pharmaceutically acceptable salt thereof, whenmeasured by a USP 27 Apparatus Type II Paddle Method @ 50 RPM in 900 mlwater at 37±0.5° C., of less than about 70% by weight tranexamic acid orpharmaceutically acceptable salt thereof released at about 45 minutesand about 100% by weight of said tranexamic acid or pharmaceuticallyacceptable salt thereof released by about 120 minutes.

A “controlled release oral dosage form” for purposes of the presentinvention is a dosage form which releases all of the active ingredient(e.g., tranexamic acid) included therein after about 4 hours or morewhen measured in vitro utilizing the USP 27 Apparatus Type II PaddleMethod @ 50 RPM in 900 ml water at 37±0.5° C.

The term “C_(max)” unless otherwise indicated is meant for purposes ofthe present invention to mean the maximum plasma concentration of amedicament achieved after single dose administration of a dosage form,or the maximum plasma concentration of a medicament achieved over adosing interval from multiple-doses at steady-state in accordance withthe present invention.

The term “T_(max)” is meant for purposes of the present invention tomean the elapsed time from administration of a dosage form to the timethe C_(max) of the medicament is achieved.

The term “steady state” means that the amount of the drug reaching thesystem is approximately the same as the amount of the drug leaving thesystem. Thus, at “steady-state”, the patient's body eliminates the drugat approximately the same rate that the drug becomes available to thepatient's system through absorption into the blood stream.

The term “mean” for purposes of the present invention, when used todefine a pharmacokinetic value (e.g., T_(max)), unless specifiedotherwise, represents the arithmetic mean value measured across apatient or subject population.

The term “three times a day (TID) basis” for purposes of the presentinvention, means that the dosage regimen is to be administered threetimes a day, preferably on a schedule of every 8 hours.

The term “mean transit time” is understood by those skilled in the artand means the time-point where 63.2% of the total AUC is attained afteroral administration, or 63.2% of the IV dose is eliminated, as describedin Applied Pharmacokinetics, Principles of Therapeutic Drug Monitoring,Second Edition (1986), edited by William E. Evans, et al., thedisclosure of which is hereby incorporated by reference in its entirety.

The term “mean absorption time” is understood by those skilled in theart and means a quantitative parameter which summarizes how long, onaverage, the drug molecule remains unabsorbed, i.e. persists in itsdosage form and in the gastrointestinal tract, also as described inApplied Pharmacokinetics, Principles of Therapeutic Drug Monitoring,Second Edition (1986), edited by William E. Evans, et al. Unlike theabsorption rate constants (ka) which can be skewed, the mean absorptiontime is not affected by incomplete release of drug from its dosage form,irregular absorption, lag-time, mixed zero-order dissolution rates,changing GI motility, GI blood flow, first-pass effect, etc.

“Therapy” for excessive menstrual bleeding is defined for the purpose ofthis invention as one or more courses of treatment with anantifibrinolytic agent such as, but not limited to, tranexamic acid,aminocaproic acid, and any pharmaceutically acceptable salts, esters,derivatives, pro-drugs, metabolites, and analogues of any of theforegoing antifibrinolytic agents.

The term “heavy menstrual bleeding” is defined for purposes of thepresent invention as a perceived blood loss of at least heavy to veryheavy which may correspond to a periodic blood loss of at least about 30ml per cycle to as much as 1000 ml per cycle as measured by the alkalinehematin test. The periodic blood loss perceived or as measured with thealkaline hematin test may vary depending on the severity of thecondition and the physiological make up of the individual patient.Therefore, heavy menstrual bleeding may include periodic blood losses ofat least about 30 ml per cycle. Losses from between about 30 ml, about40 ml, about 50 ml, about 60 ml, about 70 ml, about 80 ml, about 90 mlto about 300 ml are contemplated as are losses greater than 300 ml, suchas for example, losses between about 300 ml to about 1000 ml.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts concentration-time profiles for simulated administrationof the 1.3 g tranexamic acid modified release formulation of Example 1at a Q8H (every 8 hours) dosing schedule of 6:00 AM, 2:00 PM, 10:00 PMcomparing it with 1 g administered Q8H.

FIG. 2 depicts concentration-time profiles for simulated administrationof the 1.3 g tranexamic acid modified release formulation of Example 1at a TID (three times a day) dosing schedule of 8:00 AM, 2:00 PM, 8:00PM comparing it with 1 g administered TID.

FIG. 3 depicts mean plasma concentration-time profiles on a semi-logscale over 36 hours for the study of Example 4.

FIG. 4 depicts mean plasma concentration-time profiles on a linear scaleover 36 hours for the study of Example 4.

FIG. 5 depicts the dissolution profiles of the modified releasetranexamic acid formulation of Example 1; the immediate releasetranexamic acid formulation of Example 2; the delayed release tranexamicacid formulation of Example 3A, and the commercial Cyklokapron immediaterelease formulation of Example 4A.

FIG. 6 depicts the dissolution profile of all of the exhibit batches(Table 10A) of the modified release tranexamic acid formulations of thepresent invention and the commercial Cyklokapron immediate releaseformulation of Example 4A.

FIG. 7 is a listing of the Menorrhagia Impact Measures of the presentinvention.

FIG. 8 is a graph of Menorrhagia Instrument measure #1 percentage ofpatients and normals indicating each response at baseline (BL) and atone (1) month (M1) of Example 7.

FIG. 9 is a graph of the limitations of social and leisure activities(LSLA) in women with Heavy Menstrual Bleeding (HMB) in accordance withthe treatment regimens administered in Examples 8 and 9.

FIG. 10 is a graph of the mean menstrual blood loss change from theclinical studies of Examples 8 and 9.

DETAILED DESCRIPTION

The tranexamic acid (API) utilized in the formulations of the presentinvention is available from various manufacturers. The tranexamic acidparticles utilized in the present invention may range from about 0.1 toabout 550 microns. For example, the tranexamic acid particles may have aparticle size range from <about 0.5 to about 520 microns.

The tranexamic acid particles utilized in the present invention may havea D₂₅ particle size distribution ranging from about 5 to about 15microns, a D₅₀ particle size distribution ranging from about 14 to about73 microns, and a D₇₅ particle size distribution ranging from about 30to about 205 microns.

The particle size of the tranexamic acid utilized may also have aparticle size range wherein about 1% of the particles are of a sizegreater than about 250 microns, about 8% of the particles are of a sizeof about 180 microns, about 9% of the particles are of a size of about150 microns, about 4% of the particles are of a size of about 125microns, about 20% of the particles are of a size of about 75 microns,about 14% of the particles are of a particle size of about 45 microns,and about 44% of the particles are of a particle size less than about 45microns.

The tranexamic acid utilized may also have a particle size range whereinabout 5% of the particles are of a size greater than about 250 microns,about 12% of the particles are of a size of about 180 microns, about 14%of the particles are of a size of about 150 microns, about 14% of theparticles are of a size of about 125 microns, about 29% of the particlesare of a size of about 75 microns, about 12% of the particles are of aparticle size of about 45 microns, and about 14% of the particles are ofa particle size less than about 45 microns.

The tranexamic acid utilized may also have a particle size range whereinabout 2% of the particles are of a size greater than about 250 microns,about 7% of the particles are of a size of about 180 microns, about 9%of the particles are of a size of about 150 microns, about 4% of theparticles are of a size of about 125 microns, about 20.5% of theparticles are of a size of about 75 microns, about 16% of the particlesare of a particle size of about 45 microns, and about 41.5% of theparticles are of a particle size less than about 45 microns.

The tranexamic acid utilized may also have a particle size range whereinabout 0% of the particles are of a size greater than about 250 microns,about 5% of the particles are of a size of about 180 microns, about 12%of the particles are of a size of about 150 microns, about 11% of theparticles are of a size of about 125 microns, about 31% of the particlesare of a size of about 75 microns, about 17% of the particles are of aparticle size of about 45 microns, and about 24% of the particles are ofa particle size less than about 45 microns.

The tranexamic acid utilized may also have a particle size range whereinabout 20% of the particles are of a size of about 125 microns, about 20%of the particles are of a size of about 75 microns, about 20% of theparticles are of a particle size of about 45 microns, and about 45% ofthe particles are of a particle size less than about 45 microns.

The dosage regimen typically listed for tranexamic acid in HMB (HeavyMenstrual Bleeding) therapy is 1-1.5 g per dose administered three-fourtimes a day at the onset of copious menstrual bleeding and continued forthe first 3-5 days of the menstrual cycle. However, the most frequentlyreported dosage regimen of tranexamic acid is an immediate release oralformulation in which 1 g tranexamic acid is administered four times aday (4 g per day) for HMB therapy outside of the US. Knowledge of thiscommon regimen is supported by a careful review of the randomizedcontrolled trials published in the medical literature, product labelingfrom other countries' regulatory authorities having the product approvedfor HMB therapy, utilization data from Sweden (Rybo 1991),correspondence and interviews with non-US clinicians having experiencewith the product. That regimen is currently the dosage being studied bythe US Center for Disease Control (CDC) in women with HMB associatedwith bleeding disorders.

The absolute bioavailability of tranexamic acid observed whenadministering the European commercial formulation (Cyklokapron, Kabi AB,Sweden Batch 90288; assay 499 mgm/tablet) to male subjects isapproximately 35% and its elimination correlates with renal creatinineclearance. Peak serum tranexamic acid concentrations occur approximately3 hours after the oral administration of a European immediate-releasetablet formulation (>85% dissolved at 15 minutes) (Pilbrant, et al.,Eur. J. Clin. Pharmacol, (1981)-20:65-72). By comparison, the in vivoabsorption profile observed with the European immediate-releaseformulation is slow and very gradual over 3 hours. Specifically,tranexamic acid serum concentrations are 9, 41, 73, 88 percent (withfood), and 22, 63, 85, and 98 percent (fasting) of maximal absorption at0.5, 1, 1.5 and 2 hours after a 2 g oral dose, respectively. Althoughnot wishing to be held to any specific theory, it is presentlyhypothesized that tranexamic acid oral absorption appears to becontrolled by a non-dissolution rate limited process, i.e. the rate andextent of oral absorption is a function of a transmembranepassage-limited process, in order to explain the disparity between thetime of product dissolution and relatively prolonged tmax (time toachieve the peak serum concentration).

Preferably, the goal of the formulation, dose strength and dosageregimen of the invention, is to provide HMB therapy which achieves fromabout 20% to 100% reduction in menstrual blood loss per menstrual cycle.In accordance with certain embodiments of the present invention, thepreferred tranexamic acid dose of 1.3 g every 8 hours is predicted toprovide an average serum tranexamic acid concentration comparable tothat produced by a 1 g every 6 hour regimen (i.e. 12.4 mcg/mL), withassociated peaks and troughs falling approximately within thetherapeutic antifibrinolytic range (5-15 mcg/mL; Cyklokapron NDA19-280). In certain embodiments, a two-compartment oral absorption andelimination simulation model coupled with pharmacokinetic data(Pilbrant, et al., Eur. J. Clin. Pharmacol, (1981)-20:65-72), andmodified-release tablet dissolution performance information were used todetermine the preferred lead dosage regimen.

In immediate release formulations the entire dose and the solublecomponents in the dosage form dissolve in gastrointestinal fluid andpresent a high concentration of solutes for absorption. The mostfrequently reported adverse effects are primarily confined to theproximal gastrointestinal tract (nausea and vomiting). These adversesymptoms appear to be related to the drug load presented to the gastricmucosa, since this effect can be minimized by reducing theimmediate-release oral formulation dose or administering the productslowly by the intravenous route. In certain embodiments, a lowerincidence of proximal gastrointestinal adverse effects is obtained withthe preferred oral modified release formulation (e.g., dosed 1.3 g every8 hours) of the invention, e.g., because of the modified releaseproperties of the drug product formulation.

In certain embodiments, the oral dosage form of the present inventionprovides for an increased bioavailability as compared to immediaterelease oral dosage forms currently available (e.g., Cyklokapron). Incertain preferred embodiments the increased bioavailability allowstherapeutic plasma levels of tranexamic acid to be reached with a lowerdose of drug. Preferably, the increased bioavailability also decreasesthe amount of tranexamic acid that remains unabsorbed in thegastrointestinal which leads to decreased incidence of side effects thatare typically associated with formulations that provide higher levels ofunabsorbed tranexamic acid and prolonged exposure of thegastrointestinal tract to the higher tranexamic acid levels. Preferablythe oral dosage form of the present invention provides for abioavailability of tranexamic acid of greater than 40%, from about 41%to about 60%, preferably from about 42% to about 50%, more preferablyabout 45% after oral administration to humans.

The modified release oral formulations of tranexamic acid of the presentinvention provides a release of the drug which is slower than that ofthe immediate release 500 mg Cyklokapron product current marketed inCanada which provided a mean release rate of 100% by weight tranexamicacid released by about 15 minutes when measured utilizing USP 27Apparatus Type II paddle method @ 50 RPM in 900 ml water at 37±0.5° C.

In certain embodiments, the modified release oral formulations may bedescribed as providing a mean transit time through the proximalgastrointestinal mucosa which takes approximately one half hour longerthan an immediate release formulation. In other preferred embodiments,the modified release formulations of the invention provide a rate ofrelease of (dissolved) tranexamic acid from the dosage form in-vitrowhich is approximately 20, 40, 60, 80, and 100 percent of the total doseat 0.25, 0.5, 0.75, 1 and 1.5 hours, respectively. In certain preferredembodiments, such a release rate in-vitro demonstrates that theformulations of the present invention provide a relative reduction inthe amount and rate of dissolved tranexamic acid presented to theproximal gastric mucosa to approximate 20, 40, 60, 80, and 100 percentof the total dose at 0.25, 0.5, 0.75, 1 and 1.5 hours, respectively,after oral administration.

In certain embodiments, the majority of tranexamic acid absorptionappears to occur slowly distal to the stomach, and assuming linearpharmacokinetics, the modified release formulation produces anabsorption profile which is comparable to that achieved with thecurrently available oral immediate release formulations used outside theU.S.

In accordance with the present invention a modified release tranexamicacid tablet for oral administration is disclosed. Preferably, the tabletcontains at least one material (defined herein as any substance otherthan the active, i.e., tranexamic acid) which minimizes or eliminatesthe adverse gastrointestinal side effects in patients, for example,women dosed with oral tranexamic acid for treatment of menorrhagia.

The modified release oral dosage forms of tranexamic acid for purposesof the present invention include formulation ingredients and/orconfigurations which are typically utilized for formulations known inthe art as extended, sustained and controlled release formulations,although modified to provide a desirable release rate in keeping withthe teachings of the present invention. The modified releaseformulations preferably decrease the concentration of tranexamic acidand materials dissolved in the stomach fluids after dosing bycontrollably releasing tranexamic acid over a period of time, as opposedto immediate release formulations which release the entire dose oftranexamic acid all at once. The modified release formulations of thepresent invention thus minimize or prevent gastrointestinal reactionsand side effects that occur when a dose of tranexamic acid is ingestedand immediately reaches the stomach.

The modified release dosage forms of the present invention may beprepared as; tablets, capsules, granules, pellets, powders, dragees,troches, non-pariels, pills or encapsulated suspension, and may bepackaged into capsules, sachets, etc. Such dosage forms may be preparedby any formulation technique where release of the active substance(tranexamic acid) from the dosage form is modified to occur at a slowerrate than from an immediate release product. In these formulations,tranexamic acid release occurs in the stomach and/or intestine, but at aslower rate so that a bolus of dissolved drug does not reach the liningof the stomach and cause adverse effects, or adverse effects occur witha lower intensity or frequency because of the lower concentration oftranexamic acid. Hence, adverse effects are preferably reduced,minimized or eliminated.

Methods of preparing modified release formulations are found in ModifiedRelease Drug Delivery Technology, Rathbone, Hadgraft, and Roberts, Eds.,Drugs and the Pharmaceutical Sciences, Vol. 126, Marcel Dekker Inc., NewYork, 2003; Modern Pharmaceutics, Third Edition, Banker and Rhodes, Eds.Drugs and the Pharmaceutical Sciences, Vol. 72, Marcel Dekker Inc., NewYork, 1996; Sustained and Controlled Release Drug Delivery Systems,Robinson, Ed., Drugs and the Pharmaceutical Sciences, Vol. 6, MarcelDekker Inc., NY 1978; Sustained Release Medications, Chemical TechnologyReview No. 177, Johnson, Ed., Noyes Data Corporation 1980; ControlledDrug Delivery, Fundamentals and Applications, Second Edition, Robinsonand Lee, Eds., Marcel Dekker Inc., New York, 1987, and as described inU.S. Pat. No. 6,548,084, each of these references being expresslyincorporated by reference herein in its entirety.

Preferably, a modified release form, makes tranexamic acid availableover an extended period of time after ingestion. Modified release dosageforms coupled with the digestion process and the absorption process inthe gastrointestinal tract cause a reduction in the amount of tranexamicacid in solution in the gastrointestinal tract compared to dosingtranexamic acid presented as a conventional dosage form (e.g., as asolution, or as an immediate release dosage form). The modified releaseformulation may be verified by in vitro dissolution testing and in vivobioequivalence documentation, according to Food and Drug Administrationstandards, e.g., as set forth at www.fda.gov, 21 CFR §314, 320, and alsoat USP 23 NF 18 §711, 724. For example, an in vitro dissolution testsuch as USP 27 Apparatus Type II Paddle Method @ 50 RPM in 900 ml waterat 37±0.5° C. may be used to verify the release of the tranexamic acidfrom the dosage form.

Tranexamic acid modified release tablets may be formulated to provide adose of tranexamic acid, typically about 500 mg to about 2 grams fromone to two tablets, within about the first one to two hours after thetablet is ingested. Thus, tranexamic acid release occurs at a designedrate over a period e.g., about 60 minutes to about 120 minutes. The rateof tranexamic acid release over this period of time is designed toprovide a reduced concentration of tranexamic acid in the stomach whileallowing the absorption of tranexamic acid to occur throughout thegastrointestinal tract. Absorption of tranexamic acid typically beginsas soon as tranexamic acid is released from the dosage form and isdissolved in the gastrointestinal fluids contacting the membranes whichline the gastrointestinal tract. The rate of release of tranexamic acidfrom the dosage form and the absorption of drug by the gastrointestinalmucosa help to maintain low concentrations of drug in thegastrointestinal fluids. The lowered concentrations preferably result inlower intensity, frequency, and/or severity of gastrointestinal adverseside effects. The designed rate of release of tranexamic acid from thedosage form in the stomach and the upper small intestine, the naturalemptying of gastric juice containing any dissolved tranexamic acid fromthe stomach, and the absorption of tranexamic acid from a larger segmentof the gastrointestinal tract (i.e., both the stomach and the smallintestine, rather than the stomach only or the lower portion of thesmall intestine if any modified release dosage form with a longerrelease time was used), preferably results in reduced levels ofdissolved tranexamic acid in the region of the gastrointestinal tractproximal or distal to the dosage form. Reduced concentrations oftranexamic acid along the gastrointestinal tract preferably provide areduction in adverse gastrointestinal effects associated with oraltranexamic acid therapy.

As used herein, alleviation of adverse effects using these formulationsindicates any relief in one or more symptoms, such as decrease inincidence, severity, or duration of symptoms, and is not limited toabsence of symptoms or elimination of symptoms. Thus, treatment includesany decrease in incidence, duration, intensity, frequency, etc. ofadverse gastrointestinal symptoms including, but not limited to,headache, nausea, vomiting, diarrhea, constipation, cramping, bloating,and combinations thereof. The formulations may reduce symptoms at anytime during tranexamic acid therapy, but minimized adverse effects areparticularly noted immediately or shortly after dosing, that is, withinthe first few hours after dosing. As used herein, adversegastrointestinal effects and side effects are used interchangeably toindicate nontherapeutic effects (i.e., not relating to any possiblebeneficial effects due to tranexamic acid), ranging from unpleasant buttolerable sensations to severe gastrointestinal symptoms. As usedherein, the terms oral formulations, ingestable formulations, and orallyadministered formulations are used interchangeably and include anydosage forms which are ingested by mouth, including, but not limited to,tablets, pills, liquids, gelcaps, softgels, dragees, capsules, powders,granules, pellets, etc.

Modified release formulations of tranexamic acid include tablets,pellets, granules, capsules, or other oral dosage forms prepared in sucha way to release tranexamic acid in a designed manner. In certainembodiments, the modified release material is a gel-forming polymer, ahydratable polymer, a water soluble polymer, a water swellable polymer,or mixtures thereof.

In certain embodiments, modified release tranexamic acid tablets areprepared by adding a modified release material comprising a gel-formingor hydratable polymer to a tranexamic tablet composition. Suitablegel-forming or hydratable polymers include, but are not limited to,hydroxyproplycellulose, hydroxypropylmethylcellulose or hypromellose,carboxymethylcellulose, polyvinyl alcohol, etc. This provides acompressed tablet that may or may not be film coated. The tabletreleases tranexamic acid by diffusion of tranexamic acid through thetablet matrix, or by erosion of the tablet matrix, or by a combinationof diffusion from and erosion of the tablet matrix. Tablets formed withwater swellable polymers release tranexamic acid by diffusion oftranexamic acid through the tablet matrix, or by erosion of the tabletmatrix, or by a combination of diffusion from and erosion of the tabletmatrix. One or more water-soluble hydrophilic polymer(s) may also beused. These include polyvinylpyrrolidine, hydroxypropyl cellulose,hydroxypropylmethylcellulose, now referred to as hypromellose (e.g.,Methocel™, Dow Chemical Company), methyl cellulose, vinylacetate/crotonic acid copolymers, methacrylic acid copolymers, maleicanhydride/methyl vinyl ether copolymers, derivatives thereof andmixtures thereof. In various embodiments, the polymer is hydroxypropylcellulose or hydroxypropylmethylcellulose. The polymer may behydroxypropyl-methyl cellulose with a viscosity ranging from about 50cps to about 200 cps. The polymer may be hydroxypropyl-methyl cellulosewith a viscosity of 100 cps, commercially available as Methocel™ K 100LV (Dow Chemical Company). The amount of polymer in the composition maybe in the range of about 5% by weight to about 50% by weight of thecomposition. In various embodiments, the polymer is in the range ofabout 10% by weight to about 35% by weight of the composition, or about10% by weight to about 30% by weight of the composition.

In certain embodiments the modified release material comprises a vinylpolymer, phthalic acid derivative of vinyl copolymer,hydroxyalkylcellulose, alkylcellulose (e.g., ethylcellulose), celluloseacetate, hydroxyalkylcellulose acetate, cellulose ether, alkylcelluloseacetate and partial esters thereof, and polymers and copolymers of loweralkyl acrylic acids and lower alkyl acrylates and partial estersthereof, or combination thereof. In preferred embodiments the modifiedrelease material comprises hydroxypropylcellulose,hydryoxpropylmethylcellulose, carboxymethylcellulose, polyvinyl alcohol,polyvinylpyrrolidone, methylcellulose, vinyl acetate/crotonic acidcopolymers, methacrylic acid copolymers, maleic anhydride/methyl vinylether copolymers, derivatives thereof, and mixtures thereof. In furtherpreferred embodiments the modified release material comprises a polymersuch as a methacrylic acid copolymer. These are copolymers ofmethacrylic acid with neutral acrylate or methacrylate esters such asethyl acrylate or methyl methacrylate.

In certain embodiments the modified release material comprises a pHindependent binder or film-forming agent such as hydroxypropylmethycellulose, hydroxypropyl cellulose, methylcellulose,polyvinylpyrrolidone, neutral poly(meth)acrylate esters (e.g., themethyl methacrylate/ethyl acrylate copolymers sold as Eudragit® (RohmPharma), starches, gelatin, sugars such as glucose, sucrose, andmannitol, silicic acid, carboxymethylcellulose, and the like, diluentssuch as lactose, mannitol, dry starch, microcrystalline cellulose andthe like, surface active agents such as polyoxyethylene sorbitan esters,sorbitan ethers, and the like, coloring agents, flavoring agents,lubricants such as talc, calcium stearate, and magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, and other tableting aids.Any combination of the aforementioned binders or film-forming agents maybe included in the modified release material. The modified releasematerial may be combined with tranexamic acid to form modified releasedosage forms.

In certain embodiments, the formulation includes tranexamic acid in therange of about 50% by weight to about 95% or more by weight of theformulation. In other embodiments, tranexamic acid is in the range ofabout 60% by weight to about 90% by weight, or about 60% by weight toabout 80% by weight of the formulation. The remaining weight may be madeup of the modified release material and additional excipients.

To prepare modified release tablet formulations, the agent or modifiedrelease material to slow the release of tranexamic acid may beincorporated into the tablet matrix or coated onto the tablet surface orboth. In certain embodiments, tablet formulations prepared areformulated by granulating a blend of powders of the modified releasematerial. The powder blend is formed by combining portions of thepowdered components that make up the tablet. These powders areintimately mixed by dry-blending. The dry blended mixture is granulatedby wet mixing of a solution of a binding agent with the powder blend.The time for such wet mixing may be controlled to influence thedissolution rate of the formulation. For example, the total powder mixtime, that is, the time during which the powder is granulated, may rangefrom about 1 min to about 10 min, or from about 2 min to about 5 min.Following granulation, the particles are removed from the granulator andplaced in a fluid bed dryer, a vacuum dryer, a microwave dryer, or atray dryer for drying. Drying conditions are sufficient to removeunwanted granulating solvent, typically water, or to reduce the amountof granulating solvent to an acceptable level. Drying conditions in afluid bed dryer or tray dryer are typically about 50 to 70° C. Thegranulate is dried, screened, mixed with additional excipients such asdisintegrating agents, flow agents, or compression aids and lubricantssuch as talc, stearic acid, or magnesium stearate, and compressed intotablets.

In certain embodiments, the tablet that contains a modified releasematerial within the tablet matrix may be coated with an optionalfilm-forming agent. This applied film may aid in identification, mask anunpleasant taste, allow desired colors and surface appearance, provideenhanced elegance, aid in swallowing, aid in enteric coating, etc. Theamount of film-forming agent may be in the range of about 2% tabletweight to about 4% tablet weight. Suitable film-forming agents are knownto one skilled in the art and include hydroxypropyl cellulose, celluloseester, cellulose ether, one or more acrylic polymer(s), hydroxypropylmethylcellulose, cationic methacrylate copolymers (diethylaminoethyl)methacrylate/methyl-butyl-methacrylate copolymers such as Eudragit E®(Rohm Pharma) and the like. The film-forming agents may optionallycontain colorants, plasticizers, fillers, etc. including, but notlimited to, propylene glycol, sorbitan monooleate, sorbic acid, titaniumdioxide, and one or more pharmaceutically acceptable dye(s).

In certain embodiments, the tranexamic acid tablets of the invention arecoated with a modified release material. In certain embodiments,tranexamic acid tablets are formulated by dry blending, rotarycompacting, or wet granulating powders composed of tranexamic acid andtablet excipients. These powders are compressed into an immediaterelease tablet. Coating this immediate release tablet with a modifiedrelease material as described herein renders this tranexamic acid tabletas a modified release tablet.

In addition to the modified release material, the formulations of theinvention may also contain suitable quantities of other materials, e.g.preservatives, diluents (e.g., microcrystalline cellulose), lubricants(e.g., stearic acid, magnesium stearate, and the like), binders (e.g.,povidone, starch, and the like), disintegrants (e.g, croscarmellosesodium, corn starch, and the like), glidants (e.g., talc, colloidalsilicon dioxide, and the like), granulating aids, colorants, andflavorants that are conventional in the pharmaceutical art. Specificexamples of pharmaceutically acceptable excipients that may be used toformulate oral dosage forms are described in the Handbook ofPharmaceutical Excipients, American Pharmaceutical Association (2003),incorporated by reference herein.

The release process may be adjusted by varying the type, amount, and theratio of the ingredients to produce the desired dissolution profile, asknown to one skilled in the art. A coating may be a partiallyneutralized pH-dependent binder that controls the rate of tranexamicacid dissolution in aqueous media across the range of pH in the stomach,which has a pH of about 2, and the intestine, which has a pH of about5.5 in its upper region. In certain embodiments, one or more pHdependent binders may be used to modify the dissolution profile so thattranexamic acid is released slowly and continuously as the formulationpasses through the stomach and/or intestines.

In one embodiment, compressed modified release tablets are formulated tocomply with USP criteria and to be of such a size and shape to be easyto swallow. The size of the tablet will depend upon the dose oftranexamic acid that is needed to provide adequate therapy and theparticular formulation and excipients that are selected to provide thephysical properties necessary for tableting and for modified release. Invarious embodiments, a compressed modified release tablet contains fromabout 500 mg to about 1 gram of tranexamic acid, or from about 600 mg toabout 750 mg of tranexamic acid. The daily dose of tranexamic acid maybe achieved by taking one or two tablets at each dosing time.

In certain embodiments, the tranexamic acid included in the dosage formis from about 375 mg to about 1500 mg, preferably from about 375 mg toabout 1000 mg. In one embodiment, the dose of tranexamic acid per tabletis in the range of about 500 mg to about 1000 mg for tablets and fromabout 500 mg to about 1500 mg for a sachet filled with granules. Inanother embodiment, the dose of tranexamic acid is in the range of about3 grams/day to about 6 grams/day in three or four divided doses. As anexample, a total daily dose of 3 grams tranexamic acid may be dividedinto three doses of one tablet each with each tablet containing 1 gramtranexamic acid, or may be divided into four doses of one tablet eachwith each tablet containing 0.75 gram tranexamic acid. As anotherexample, a total daily dose of 4 gram tranexamic acid may be dividedinto three doses of two tablets at each dose with each tablet containing0.666 gram tranexamic acid, or may be divided into four doses of onetablet each with each tablet containing 1 gram tranexamic acid. Asanother example, a total daily dose of 5 gram tranexamic acid may bedivided into three doses of one tablet each with each tablet containing1.66 gram tranexamic acid, or may be divided into four doses of twotablets each with each tablet containing 0.625 gram tranexamic acid. Asanother example, a total daily dose of 6 gram tranexamic acid may bedivided into three doses of two tablets each with each tablet containing1 gram tranexamic acid, or may be divided into four doses of two tabletseach with each tablet containing 0.75 gram tranexamic acid. For ease ofswallowing, the dose of tranexamic acid taken at each dosing time may bedelivered by taking multiple tablets. For example, the 4 gram daily dosemay be delivered by taking two 666.67 mg tablets three times a day ortwo 500 mg tablets four times a day. Similarly, the 3 gram daily dosemay be achieved by taking two 550 mg tablets three times a day or two375 mg tablets four times a day. Alternatively, for ease of reference, adose of 600 mg, 650 mg, or 700 mg of tranexamic acid per tablet may beused. In a preferred embodiment, a total daily dose of 3900 mg/day isadministered in three divided doses of 1300 mg of two tablets at eachdose with each tablet containing 650 mg of tranexamic acid.Alternatively, each dose may be delivered by taking granules containingthe prescribed amount of tranexamic acid presented in a convenient unitdose package. Such examples are not limiting and other doses withinthese ranges will be appreciated by those skilled in the art.

Since tranexamic acid is primarly eliminated via the kidneys byglomerular filtration with more than 95% excreted unchanged drug in theurine, dosage adjustment may be recommended. The table below lists somerecommended dosage adjustments for renal impairment:

Serum Estimated Creatinine GFR* Total (mg/dl) (ml/min) Adjusted dosedaily dose 1.4 to 2.8 30-60 1.3 g (two 650 mg tablets) BID 2.6 g 2.8 to5.7 15-30 1.3 g (two 650 mg tablets) QD 1.3 g >5.7 <15 1.3 g (two 650 mgtablets) every 0.65 g  48 hours or 650 mg (one tablet) every 24 hours

Alternatively, modified release tranexamic acid formulations may beadministered by pellets or granules in e.g., a sachet or capsule.Modified release tranexamic acid pellets or granules may be prepared byusing materials to modify the release of tranexamic acid from thegranule or pellet matrix. Modified release preparations may also beformulated using coatings to modify the release of tranexamic acid fromthe granule or pellet. U.S. Pat. Nos. 5,650,174; and 5,229,135 each ofwhich is expressly incorporated by reference herein in its entirety,disclose variations on fabricating a pellet or nonpareil dosage form.Spheres are filled into packets, termed sachets, or capsules which arefilled by weight to contain the prescribed dose of drug.Multiparticulates may be coated with an modified release coating, asdisclosed in U.S. Pat. No. 6,066,339, which is expressly incorporated byreference herein its entirety. Coated multiparticulates may be packagedin capsules or sachets. The formulation of granules or pellets formodified release is described in Multiparticulate Oral Drug Delivery,Ghebre-Sellassie, Ed. in Drugs and the Pharmaceutical Sciences, Vol. 65Marcel Dekker Inc. NY, 1994 and in the relevant parts of the referencesfor modified release formulations previously cited and the relevantportions incorporated herein by reference.

Additional tranexamic acid formulations are disclosed in U.S. patentapplication Ser. No. 12/220,241, filed Jul. 23, 2008; and Ser. No.11/346,710, filed Feb. 3, 2006, the disclosures of which are herebyincorporated by reference in their entirety.

In certain embodiments, the inventive tranexamic acid formulations maybe used for additional indications other than menorrhagia, such asconization of the cervix, epistaxis, hyphema, hereditary angioneuroticedema, a patient with a blood coagulation disorder undergoing dentalsurgery, combinations thereof, and the like.

Menorrhagia Instrument

With regard to the treatment of menorrhagia (Heavy Menstrual Bleeding)studies of the safety and efficacy of the antifibrinolytic tranexamicacid were conducted. As part of these studies a diagnosis and treatmentinstrument (Mnorrhagia Instrument; MI) was designed. The instrumentreliably identifies and monitors heavy menstrual bleeding patients andcan be used in conjunction with an antifibrinolytic agent to diagnoseand monitor the treatment of heavy menstrual bleeding.

A Menorrhagia Instrument (MI) of the invention reliably captures thediagnosis and treatment of the disease by measuring the impact oftreatment on the symptoms associated with heavy menstrual bleeding. Theinformation obtained from individual patient responses to the measuresdescribed in the methods of the present invention correlates to bloodloss as measured by the alkaline hematin test. For example, data fromthe measures of social, leisure and/or physical activity symptoms,correlate with the volume of blood loss, and the change in the intensityof these symptoms correlates with the change in volume of blood lost,thus providing a measurement for the successful diagnosis and evaluationof treatment of bleeding disorders.

The instrument of the present invention measures specific aspects of thepatient's monthly menstrual period. The measures correlate with thediagnosis of heavy menstrual bleeding and with the course ofantifibrinolytic treatment. Further each of the measures individuallycorrelate with quantity of blood loss as measured by the alkalineHematin test. The symptomatic measures include: 1) a functionalassessment measure; and ii) a pharmacology (or therapy assessment)measure.

The functional assessment measure of symptoms is further factored intosegments which include 1) a measure of functional impairment generally;2) impairment of necessary activities; and 3) impairment ofdiscretionary activities.

The pharmacology domain provides an assessment of the severity of themenstrual period.

Specific symptomatic measures may be directed to an initial patientassessment and to the treatment period (pharmacology measure). Examplesof specific measures would include examples of initial patientassessment measures (measures 1-4 listed in the Menorrhagia Instrumentof FIG. 7); and therapy assessment measures (measures 1-4 together withmeasures 6, 6a, 6b and 6c contained in the Menorrhagia Instrument ofFIG. 7).

In certain embodiments, the present invention is directed to a method ofdiagnosing and treating heavy menstrual bleeding, wherein the initialdiagnoses of heavy menstrual bleeding is accomplished by evaluation ofthe most recent menstrual period on the basis of one, some or all of theprescribed symptomatic measures of FIG. 7. Measures which may be used aspart of the initial patient assessment include, for example: a)determining a patient's perceived blood loss during their most recentmenstrual period; b) determining how much the patient's blood losslimited their work outside and inside the home; c) determining how muchthe patient's blood loss limited their physical activities; d)determining how much the patient's blood loss limited their social andleisure activities; and e) determining the specific activities that werelimited by the patient's blood loss.

The assessment of the patient's perceived blood loss during their mostrecent menstrual period may include an inquiry such as “during your mostrecent menstrual period, your blood loss was”. The assessment may thenquantify the patient response as a blood loss that was: i) light, ii)moderate, iii) heavy, or iv) very heavy. Alternatively, the measure maybe quantified in terms of a scale of from one to four where onerepresents light, two represents moderate, three represents heavy andfour represents very heavy.

The assessment of a patient's limitation due to the blood loss mayinclude and evaluation of the patient's blood loss limitation onphysical activities and/or how much the patient's blood loss limitedtheir social and leisure activities. Assessment of the limitations onwork, physical, social and leisure activities may be quantitated as: i)not at all, ii) slightly, iii) moderately, iv) quite a bit, or v)extremely. Alternatively the measure may be quantified in terms of ascale of from one to five where one represents not at all, tworepresents slightly, three represents moderately, four represents quitea bit, and five represents extremely.

Activities limited may include, but are not limited to, walking,standing, climbing stairs, squatting or bending down, playing withchildren and attending school activities. Home management activitiesinclude, but are not limited to, cooking, cleaning, yard work, andlaundry. Leisure activities may include, but are not limited to,dancing, dinner, and movies. Sports activities may include, but are notlimited to, tennis, golf, running, swimming, hiking, biking, boating,baseball, softball, basketball, soccer, fencing, volleyball, and othersports related activities.

Once the initial patient assessment measures have been completed and thepatient has been identified as in need of treatment, the patient isadministered a therapeutically effective treatment regimen of anantifibrinolytic agent. Suitable antifibrinolytic agents contemplatedfor use in the present invention include, but are not limited totranexamic acid, aminocaproic acid, pharmaceutically acceptable salts,esters, derivatives, pro-drugs, metabolites, and analogues of any of theforegoing antifibrinolytic agents.

In certain embodiments the preferred antifibrinolytic agent istranexamic acid. The tranexamic acid utilized in the present inventioncan be formulated into any suitable dosage form. Preferably, thetranexamic acid is in the form of a release modified tranexamic acidformulation.

When the preferred antifibrinolytic is tranexamic acid, thetherapeutically effective treatment regimen contemplated by the presentinvention includes administration of a single dose of a tranexamic acidranging from about 650 mg to about 1300 mg three (3) times a day for atleast one day of menstruation, but not more than five days (or 15 singledoses). The treatment regimen may be administered for at least one day;for at least the first two days, for at least the first three days, fordays two through three, for days two to three, for the duration ofmenstruation.

In certain embodiments the tranexamic acid treatment regimen fortreating the heavy menstrual bleeding includes administration of asingle dose of about 650 mg to about 1.3 gm of a modified releaseformulation three (3) times a day, wherein the modified releaseformulation contains the tranexamic acid in combination with a modifiedrelease material

In certain other embodiments, the present invention is directed to amethod of evaluating the effectiveness of a treatment regimenadministered for heavy menstrual bleeding.

Evaluation of the effectiveness of the treatment regimen can beinitiated at the end of the patient's menstrual period, but prior tocompletion of the menstrual cycle. The post-menstruation measuresprovide in part the pharmacology (or therapy assessment) measuredescribed above.

The pharmacology assessment may begin with one or more of the sameseries of measures utilized during the initial patient assessment, whichinclude: a) determining a patient's perceived blood loss volume duringtheir most recent menstrual period; b) determining how much thepatient's blood loss limited their work outside and inside the home; c)determining how much the patient's blood loss limited their physicalactivities; d) determining how much the patient's blood loss limitedtheir social and leisure activities; e) determining the specificactivities that were limited by the patient's blood loss.

Alternatively, an evaluation of the effectiveness of the treatmentregimen may require determining the change in the patient's perceivedblood loss during the most recent menstrual period in comparison to theblood loss during the patient's previous menstrual period, measure 1 ofFIG. 7 and/or an assessment of the improvement achieved, measure 6 ofFIG. 7.

For example, a change in the patients perceived blood loss of about oneunit for example from “heavy” to “moderate” or from a score of 3(“heavy”) to a score of 2 (“moderate”) would provide the basis forcontinued treatment. While a perceived loss of less than one unit wouldsuggest either a discontinuation of treatment or a second course afterwhich the evaluation would be reconsidered. Alternatively, or inaddition to the blood loss assessment, the practitioner may rely on theassessment in which the comparison of perceived loss is assessed as: i)“about the same”, ii) “better”, and iii) “worse”, as prescribed inmeasure 6 in FIG. 1. When a patient's response is “about the same”, analternative treatment regimen may be considered for the next menstrualperiod. The practitioner may also reconsider re-administering the sametreatment regimen for an additional menstrual period and laterre-evaluate. When a patient's response is “better”, the assessment maycontinue by requiring the patient to provide further information aboutthe improvement in menstrual bleeding. For example, the assessment mayinclude “if your menstrual bleeding improved since your last period,please indicate how much” (measure 6b of the MI of FIG. 7). Answers tothis inquiry about an improvement in menstrual bleeding may require thepatient to provide an answer such as: i) a very great deal better; ii) agreat deal better; iii) a good deal better; iv) an average amountbetter; v) somewhat better; vi) a little better; or vii) almost thesame, hardly better at all. Alternatively the answers can be scaled on aseven unit scale where “a very great deal better” is assigned a value of7 and “almost the same” is valued as 7.

When a patient's response to measure 6 is “worse”, the inquiry continuesby requiring the patient to provide further data characterizing thechange in menstrual bleeding. For example, the inquiry may determine “ifyour menstrual period worsened since your last period, please indicatehow much” (measure 6c of MI of FIG. 7). Data for this measure to aworsening in menstrual bleeding may require the patient to provide aranking such as: i) “a very great deal worse”; ii) “a great deal worse”;iii) “a good deal worse”; iv) “an average amount worse”; v) “somewhatworse”; vi) “a little worse”; or vii) “almost the same, hardly worse atall”. As before the answers may be scaled on a seven unit scale where −1is “almost the same” and −7 is “a very great deal worse”.

The comparison of perceived blood loss which results in an improvementof at least one unit as measured by measure 1 of FIG. 7 and/or anassessment of a perceived blood loss which is “better” as provided inmeasure six of FIG. 1 may proceed by assessing whether the improvement“was a meaningful or an important change” to the patient (measure 6c ofMI of FIG. 7).

The information obtained about the “improvement” or “worsening” inmenstrual bleeding allows the practitioner to make an evaluation of theeffectiveness of the treatment regimen which correlates with the changein blood loss as measured by the alkaline hematin test and demonstratedwith clinical trial data.

The method for evaluating the effectiveness of a treatment regimen ofthe present invention may be repeated after each menstrual period. Thedata obtained from the initial patient assessment and the subsequentpharmacology (therapy assessment) can be stored into a computer databaseand utilized for future diagnostic and/or evaluation purposes.

In certain other embodiments, the present invention is directed to amethod of treating heavy menstrual bleeding. The method involving,evaluating symptomatic data gathered from the measures individually orcollectively as described in FIG. 1. (items one through four and six asdiscussed above) to determine the need for therapy and thenadministering, to a patient in need, a therapeutically effectivetreatment regimen of an antifibrinolytic agent, e.g., a release modifiedtranexamic acid formulation, wherein the treatment regimen is to beadministered for part or for the duration of menstruation, but no longerthan 5 days during the patient's menstrual cycle.

The present invention is further described with regard to the followingexamples.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The invention will be further appreciated with respect to the followingnon-limiting examples. Other variations or embodiments of the inventionwill also be apparent to one of ordinary skill in the art from the abovedescriptions and examples. Thus, the forgoing embodiments are not to beconstrued as limiting the scope of this invention.

Example 1

Modified release 650 mg tranexamic acid tablets were prepared having theingredients listed in the Table 1 below:

TABLE 1 Quantity Quantity per batch per tablet Ingredient (kg) (mg)Active Ingredient Tranexamic Acid, EP 84.50 650.0 Inactive IngredientsMicrocrystalline Cellulose NF (Avicel PH 101) 5.753 44.25 ColloidalSilicon Dioxide NF 0.0975 0.75 Pregelatinized Corn Starch, NF 6.43549.50 Hypromellose, USP (Methocel K3 Premium LV) 19.110 147.00 Povidone,USP (K value range 29-32) 4.680 36.00 Stearic Acid, NF (powder) 2.34018.00 Magnesium Stearate, NF (powder) 0.585 4.50 Purified Water USP*17.550 135.00 *Purified water is removed during processingThe formulation of Example 1 was prepared as follows:

-   1. Weigh all ingredients and keep in moisture resistant containers    until ready for use.-   2. Measure water into a container. Mix povidone at medium speed    until completely dissolved.-   3. Add tranexamic acid, microcrystalline cellulose (MCC),    pregelatinized corn starch, and colloidal silicon dioxide to the    high shear mixer.-   4. Mix using impeller only.-   5. Mix for an additional time (impeller only). Add all of the    povidone solution during this mixing step.-   6. Mix until adequately granulated (impeller and chopper). Proceed    only when desired granulation has been achieved. Add additional    water if necessary.-   7. Dry the granulation to moisture content of NMT 1.2%.-   8. Pass the granulation through the oscillating granulator equipped    with a #30 mesh screen. Weigh the granulation. Add granulation to    the V-Blender.-   9. Add the hypromellose USP Methocel K3 Premium to the V-blender.    Blend.-   10. Pass magnesium stearate and stearic acid through oscillating    granulator equipped with a #40 mesh screen. Add magnesium stearate    and stearic acid to the V-blender and blend.-   11. Perform specified physical property testing. Proceed to    compression.-   12. Compress tablets to desired weight.

Example 2

In Example 2, immediate release 650 mg tranexamic acid tablets wereprepared having the ingredients listed in Table 2 below:

TABLE 2 Quantity per batch Quantity per Ingredient (kg) tablet (mg)Active Ingredient Tranexamic Acid, EP (650 mg/tab) 84.50 650.0 InactiveIngredients Microcrystalline Cellulose, NF (Avicel 5.753 44.25 PH 101)Microcrystalline Cellulose, NF (Avicel 10.660 82.00 PH 102) ColloidalSilicon Dioxide, NF 0.0975 0.75 Pregelatinized Corn Starch, NF 6.43549.50 Croscarmellose Sodium, NF 19.50 15.00 Povidone, USP (K value range29-32) 4.680 36.00 Stearic Acid, NF (powder) 2.340 18.00 MagnesiumStearate, NF (powder) 0.585 4.50 Purified Water, USP* 17.550 135.00 FilmCoating (Inactive Ingredients)** Opadry White YS-1-7003 4.110 — PurifiedWater, USP 36.990 — *Purified water is removed during processing **6 kgexcess prepared to account for losses during transferThe formulation of Example 2 was prepared as follows:

-   1. Weigh all ingredients and keep in moisture resistant containers    until ready for use.-   2. Measure water into a container. Mix povidone at medium speed    until completely dissolved.-   3. Add tranexamic acid, microcrystalline cellulose (MCC),    pregelatinized corn starch, and colloidal silicon dioxide to the    high shear mixer.-   4. Mix using impeller only.-   5. Mix for an additional time (impeller only). Add all of the    povidone solution during this mixing step.-   6. Mix until adequately granulated (impeller and chopper). Proceed    only when desired granulation has been achieved. Add additional    water if necessary.-   7. Dry the granulation to moisture content of NMT 1.2%.-   8. Pass the granulation through the oscillating granulator equipped    with a #30 mesh screen. Weigh the granulation. Add granulation to    the V-Blender.-   9. Add the croscarmellose sodium and MCC to the V-Blender and blend.-   10. Pass magnesium stearate and stearic acid through oscillating    granulator equipped with a #40 mesh screen. Add magnesium stearate    and stearic acid to the V-blender and blend.-   11. Perform specified physical property testing. Proceed to    compression.-   12. Compress tablets.-   12. After compression, spray coat the compressed dosage forms with    the Opadry White in water.

Example 3

In Example 3, modified release 650 mg tranexamic acid tablets wereprepared as in Example 1 and coated with a film coating similar to theimmediate release tablets of Example 2. The ingredients are listed inTable 3 below:

TABLE 3 Quantity Quantity per batch per tablet Ingredient (kg) (mg)Active Ingredient Tranexamic Acid, EP 84.50 650.0 Inactive IngredientsMicrocrystalline Cellulose NF (Avicel PH 101) 5.753 44.25 ColloidalSilicon Dioxide NF 0.0975 0.75 Pregelatinized Corn Starch, NF 6.43549.50 Hypromellose, USP (Methocel K3 Premium LV) 19.110 147.00 Povidone,USP (K value range 29-32) 4.680 36.00 Stearic Acid, NF (powder) 2.34018.00 Magnesium Stearate, NF (powder) 0.585 4.50 Purified Water USP*17.550 135.00 Film Coating (Inactive Ingredients)** Opadry WhiteYS-1-7003 4.305 — Purified Water, USP 38.750 — *Purified water isremoved during processing **6 kg excess prepared to account for lossesduring transfer

Example 3A

Example 3A, delayed release 650 mg tranexamic acid tablets were preparedhaving the ingredients listed in Table 3A below:

TABLE 3A Quantity Quantity per batch per tablet Ingredient (kg) (mg)Active Ingredient Tranexamic Acid, EP 84.50 650.0 Inactive IngredientsMicrocrystalline Cellulose NF (Avicel PH 101) 5.753 44.25Microcrystalline Cellulose NF (Avivel PH 102) 10.660 82.00 ColloidalSilicon Dioxide NF 0.0975 0.75 Pregelatinized Corn Starch, NF 6.43549.50 Croscarmellose Sodium NF 19.50 15.00 Povidone, USP (K value range29-32) 4.680 36.00 Stearic Acid, NF (powder) 2.340 18.00 MagnesiumStearate, NF (powder) 0.585 4.50 Purified Water USP* 17.550 135.00 FilmCoating (Inactive Ingredients)** Acryl-Eze (930185359) 12.90 — SiliconeEmulsion, 30% 0.323 — Purified Water, USP 51.271 — *Purified water isremoved during processing; mg per tablet is based on theoreticalspecific gravity of 1.0 g/ml **6 kg excess prepared to account forlosses during transferThe formulation of Example 3A was prepared as follows:

-   1. Weigh all ingredients and keep in moisture resistant containers    until ready for use.-   2. Measure water into a container. Mix povidone at medium speed    until completely dissolved.-   3. Add tranexamic acid, microcrystalline cellulose (MCC),    pregelatinized corn starch, and colloidal silicon dioxide to the    high shear mixer.-   4. Mix using impeller only.-   5. Mix for an additional time (impeller only). Add all of the    povidone solution during this mixing step.-   6. Mix until adequately granulated (impeller and chopper). Proceed    only when desired granulation has been achieved. Add additional    water if necessary.-   7. Dry the granulation to moisture content of NMT 1.2%.-   8. Pass the granulation through the oscillating granulator equipped    with a #30 mesh screen. Weigh the granulation. Add granulation to    the V-Blender.-   9. Add the croscarmellose sodium and MCC to the V-Blender and blend.-   10. Pass magnesium stearate and stearic acid through oscillating    granulator equipped with a #40 mesh screen. Add magnesium stearate    and stearic acid to the V-blender and blend.-   11. Perform specified physical property testing. Proceed to    compression.-   12. Compress tablets.-   13. After compression, spray coat the compressed dosage forms with    the film coating.

Dissolution results for the delayed release formulation of Example 3A(in base stage) are listed below in Table 3B.

Dissolution Results for the Delayed Release Formulation In Base Stage

TABLE 3B Time (min.) Dissolution (%) Standard Deviation 15 16% ±6.01387330 89% ±14.06769 45 95% ±2.810694 60 97% ±2.345208

Example 4 Bioavailability and Bioequivalence Evaluation

In Example 4, a comparative, randomized, single dose, 4-way CrossoverAbsolute Bioavailability (BA) and Bioequivalence (BE) study ofTranexamic Acid Tablet Formulations prepared in accordance with Examples1 and 2 in Healthy Adult Women Volunteers under Fasting Conditions wasperformed. The objective was to assess the bioequivalence of a 650 mgmodified release tablet formulation prepared in accordance with Example1 compared to the immediate release reference tablet formulation oftranexamic acid prepared in accordance with Example 2, and to determinethe bioavailability of the modified tablet formulation to the approvedIV (1 g) formulation Cyklokapron® by Pharmacia & Upjohn. The design wasa randomized, 4-way crossover, comparative BE and BA determination. Alloral doses administered were 1.3 g. Twenty-eight (28) healthynon-smoking adult female volunteer subjects were enrolled in the study.A total of 26 subjects completed the study. Sample size was calculatedassuming a 25% CV in AUC_(inf). The study endpoints were the 90%confidence intervals of the ratio of least-squares means of thepharmacokinetic parameters AUC_(0-t), AUC_(inf) and C_(max) of themodified release formulation to the immediate-release formulation fromserum concentration-time data drawn up to 36 hours after a single doseof drug. In addition, the bioavailability of the tablet formulationswere calculated. Smokers, oral contraceptive users, those with aprevious history of thromboembolic events and altered vision wereexcluded from the study. ECG monitoring was performed before, during andafter the estimated times of peak serum tranexamic acid concentrationsexposure. Adverse events were captured and recorded throughout the trialperiod.

In the study, subjects were randomized to receive single oral 1.3 g(2×650 mg tablets) dose of tranexamic acid in tablet forms whichincluded a modified release dosage form and an immediate release dosageform. Subjects were also administered a single 1 g (10 ml) IV solutionof tranexamic acid (100 mg/ml concentration).

A summary of the pharmacokinetic results from the study of Example 4 arelisted in the tables below.

TABLE 4 Summary of Results - Tranexamic Acid in Plasma PharmacokineticParameters (N = 26) ln AUC 0-t* ln AUCinf* ln Cmax* (mcg · h/mL) (mcg ·h/mL) (mcg/mL) Modified Release formulation Mean 66.703 69.642 11.251088CV 26.8 27.2 29.1 N 26 24 26 Immediate Release formulation Mean 70.15772.656 12.260414 CV 16.2 16.4 23.0 N 26 24 26 Least-Squares Mean:Modified Release 66.935 68.891 11.321919 Immediate Release 70.051 72.41112.258222 Ratio of 95.6 95.1 92.4 Least-Squares Mean (modifiedrelease/immediate release)% *For ln-transformed parameters, the antilogof the mean (i.e. the geometric mean) is reported. AUCinf, kel,half-life and F could not be estimated for some subjects. AUC 0-t is thearea under the plasma concentration versus time curve, from time 0 tothe last measurable concentration, as calculated by the lineartrapezoidal method.

TABLE 5 Summary of Results - Tranexamic Acid in Plasma PharmacokineticParameters (N = 26) Tmax Half-life kel F (h) (h) (1/h) (%) ModifiedRelease formulation Mean 2.942 11.370 0.06300 44.93 CV 22.7 17.6 19.425.3 n 26 26 26 24 Immediate Release formulation Mean 2.808 11.0130.06438 46.04 CV 20.8 15.5 15.3 16.1 n 26 24 24 24

TABLE 6 Summary of Results - Tranexamic Acid in Plasma PharmacokineticParameters (N = 26) Ln AUC 0-t* ln AUCinf* ln Cmax* (mcg · h/mL) (mcg ·h/mL) (mcg/mL) 90% Confidence Intervals (Modified release/Immediaterelease)% lower limit: 87.8% 87.4% 84.0% upper limit: 104.0% 103.5%101.6% p-Value (ANOVA) Modified vs Immediate 0.3721 0.3259 0.1676 Period0.0704 0.0499 0.0356 Sequence 0.7734 0.7978 0.8207 Intrasubject CV %18.3 17.4 20.6 *For ln-transformed parameters, the antilog of the mean(i.e. the geometric mean) is reported. AUCinf, kel, half-life and Fcould not be estimated for some subjects.

Concentration-time profiles for the study of Example 4 are presented onsemi-log and linear scale over 36 hours and are depicted in FIGS. 3 and4.

The following pharmacokinetic parameters in the table below werecalculated for tranexamic acid in plasma for the study of Example 4.

-   -   MRT: The mean residence time (MRT) after intravenous        administration of tranexamic acid was determined using the        equation,    -    AUMC/AUC+infusion time/2,    -    where the AUMC is the area under the moment-time curve.    -   MTT: Following oral administration of the Modified Release and        Immediate Release formulations, the mean transit time (MTT) of        tranexamic acid was calculated by dividing the AUMC by the AUC.    -   MAT: The mean absorption time (MAT) for the two formulations was        derived by subtracting the MRT from the MTT.        Mean (±SD) results are presented in the table below:

TABLE 7 IV Modified Release Immediate Release MRT (hours) 3.51 ± 0.38N/A N/A MTT (hours) N/A 7.70 ± 0.72 7.21 ± 1.01 MAT (hours) N/A 4.18 ±0.70 3.70 ± 0.94

The mean transit time (MTT) and mean absorption time (MAT) of theModified Release formulation of tranexamic acid was approximately 30minutes longer than that observed for the Immediate Release formulation.

The most frequently reported adverse events from the study of Example 4are listed in the table below. The table lists the number of subjectsreporting adverse events, and the percentage of subjects is inparentheses.

TABLE 8 Treatment Modified Immediate IV solution Release Release (10 ×(2 × 650 mg) (2 × 650 mg) 100 mg/ml) Adverse Events (n = 27) (n = 27) (n= 27) Headache  4 (15%)  7 (26%)  7 (26%) Nausea 0 (0%) 2 (7%) 10 (37%)Dizziness 0 (0%) 0 (0%) 11 (41%) Feeling Hot 0 (0%) 0 (0%)  6 (22%)Nasal Congestion 2 (7%) 1 (4%) 1 (4%) Cough 0 (0%) 0 (0%) 2 (7%) Urineodor abnormal 2 (7%) 0 (0%) 1 (4%)

Dissolution Results for Immediate Release and Modified ReleaseFormulations prepared in accordance with Examples 2 and 1 respectivelyused in the study of Example 4 tested under USP 27 Apparatus Type IIPaddle Method @ 50 RPM in 900 ml water at 37±0.5° C. are listed in thetables below.

TABLE 9 Dissolution Results for the Immediate Release Formulation inTable 2. Time (min.) Dissolution (%) Standard Deviation 15 58.0%±9.521905 30 96.0% ±10.2697 45 102.0% ±0.408248 60 104.0% ±1.032796

TABLE 10 Dissolution Results for the Modified Release Formulation inTable 1 Time (min.) Dissolution (%) Standard Deviation 15 21.0%±1.414214 30 40.0% ±2.810694 45 58.0% ±3.600926 60 73.0% ±3.81663 9098.0% ±2.097618

TABLE 10A Dissolution Results for the Various Batches of the ModifiedRelease Formulation Table 1 0 15 45 90 Batch # min min min min StandardDeviation Batch 1 0 21 58 98 0 ±1.386 ±3.48 ±2.254 Batch 2 0 21 58 95 0±1.134 ±3.074 ±2.47 Batch 3 0 23 59 93 0 ±2.323 ±4.366 ±3.627 Batch 4 021 56 89 0 ±1.575 ±3.808 ±2.492 Batch 5 0 24 59 93 0 ±2.016 ±3.422±2.139 Batch 6 0 25 67 100 0 ±1.45 ±3.149 ±0.9 Batch 7 0 22 58 94 0±0.968 ±2.32 ±2.068 Batch 8 0 29 69 98 0 ±2.03 ±3.726 ±1.666 Batch 9 028 66 96 0 ±2.268 ±3.762 ±2.688 Batch 10 0 15 65 93 0 ±1.904 ±2.47±2.604 Batch 11 0 27 64 92 0 ±1.836 ±2.368 ±2.024

Conclusions

The ratios of least-squares means and the 90% confidence intervalsderived from the analyses of the ln-transformed pharmacokineticparameters AUC_(0-t), AUC_(inf) and C_(max) for tranexamic acid inplasma were within the 80-125% Food and Drug Administration (FDA)acceptance range for the modified release formulation versus theimmediate release formulation under fasting conditions.

The absolute bioavailability of the modified release and immediaterelease tablet formulations were 44.93% and 46.04% respectively.

Based on these results, the modified release tranexamic acid tabletformulation and the immediate release tranexamic acid formulation arebioequivalent under fasting conditions.

Example 4A Comparative Example

In Comparative Example 4A, a 500 mg immediate release tranexamic acidtablet, approved and marketed in Canada under the name Cyklokapron wasobtained and dissolution tested under USP 27 Apparatus Type II PaddleMethod @ 50 RPM in 900 ml water at 37±0.5° C. The dissolution resultsare listed in Table 10B below:

TABLE 10B % dissolved % dissolved % dissolve % dissolved Sample # in 15min. in 30 min. in 45 min. in 60 min. 1 102 104 105 106 2 102 104 105106 3 101 102 102 105 4 99 101 102 103 5 100 102 103 104 6 99 101 102104 Average 101 102 103 105 % RSD 1.4 1.3 1.4 1.1

Example 5

In Example 5, based on single dose pharmacokinetic parameters,pharmacokinetic simulations of serum concentrations were performed tocompare dosing the modified release formulation of Example 4 at every 8hours (Q8H: at 6:00 AM, 2:00 PM, 10:00 PM) and dosing three times a day,other than every 8 hours (TID: at 8:00 AM, 2:00 PM, and 10:00 PM). Theresults are provided in Tables 11-14 below.

TABLE 11 Tranexamic Acid - Modified Release Formulation Dosage RegimenSimulation - ORAL 1.3 g q8hr Time (h) Dose (mcg) Conc. (mcg/mL) 01.30E+06 0 1 0 4.0594 2 0 10.0551 3 0 10.6433 4 0 9.20306 5 0 7.26932 60 5.4699 8 1.30E+06 2.89909 9 0 6.15391 10 0 11.5813 11 0 11.7752 12 010.0646 13 0 7.94622 14 0 6.02067 15 0 4.4712 16 1.30E+06 3.30248 17 06.51406 18 0 11.9097 19 0 12.0794 20 0 10.3495 21 0 8.21523 22 0 6.276123 0 4.71463 24 1.30E+06 3.53505 25 0 6.73663 26 0 12.1229 27 0 12.283828 0 10.5455 29 0 8.40336 30 0 6.45664 31 0 4.88791 32 1.30E+06 3.7013833 0 6.89628 34 0 12.2762 35 0 12.4309 36 0 10.6868 37 0 8.53894 38 06.5868 39 0 5.01286 40 1.30E+06 3.82133 41 0 7.01144 42 0 12.3867 43 012.537 44 0 10.7887 45 0 8.63675 46 0 6.68069 47 0 5.103 48 1.30E+063.90786 49 0 7.09451 50 0 12.4665 51 0 12.6136 52 0 10.8621 53 0 8.7073154 0 6.74842 55 0 5.16802 56 1.30E+06 3.97028 57 0 7.15443 58 0 12.52459 0 12.6688 60 0 10.9152 61 0 8.7582 62 0 6.79728 63 0 5.21493 641.30E+06 4.01531 65 0 7.19766 66 0 12.5655 67 0 12.7087 68 0 10.9534 690 8.79492 70 0 6.83253 71 0 5.24877 72 1.30E+06 4.0478 73 0 7.22885 74 012.5954 75 0 12.7374 76 0 10.981 77 0 8.82141 78 0 6.85796 79 0 5.2731880 1.30E+06 4.07124 81 0 7.25135 82 0 12.617 83 0 12.7581 84 0 11.000985 0 8.84052 86 0 6.87631 87 0 5.29079 88 1.30E+06 4.08814 89 0 7.2675890 0 12.6326 91 0 12.7731 92 0 11.0153 93 0 8.8543 94 0 6.88954 95 05.3035 96 1.30E+06 4.10034 97 0 7.27929 98 0 12.6439 99 0 12.7839 100 011.0256 101 0 8.86425 102 0 6.89909 103 0 5.31266 104 1.30E+06 4.10913105 0 7.28773 106 0 12.652 107 0 12.7917 108 0 11.0331 109 0 8.87142 1100 6.90597 111 0 5.31927 112 1.30E+06 4.11548 113 0 7.29382 114 0 12.6578115 0 12.7973 116 0 11.0385 117 0 8.8766 118 0 6.91094 119 0 5.32404 1200 4.12006

Concentration-time profiles are presented over 120 hours for themodified release formulation in Table 12 and are depicted in FIG. 1. A 1g formulation administered q8h is also depicted for comparison purposes.

TABLE 12 Cmax, Cmin and Cavg for 1.3 g q8hr simulation Simulation at 120hours Pharmacokinetic Parameter Concentration Cmax 12.8 mcg/mL  Cmin 4.1mcg/mL Cavg 8.4 mcg/ml

TABLE 13 Tranexamic Acid - Modified Release Formulation Dosage RegimenSimulation - ORAL 1.3 g TID (8:00 AM, 2:00 PM, and 10:00 PM) Time (h)Dose (mcg) Conc. (mcg/mL) 0 1.30E+06 0 1 0 4.0594 2 0 10.0551 3 010.6433 4 0 9.20306 5 0 7.26932 6 1.30E+06 5.4699 8 0 12.9542 9 012.7378 10 0 10.7293 11 0 8.40129 12 1.30E+06 6.33141 13 0 8.74352 14 013.505 15 0 13.2018 16 0 11.1327 17 0 8.76144 18 0 6.65976 19 0 4.9882320 0 3.73474 21 0 2.8275 22 0 2.18502 23 0 1.73555 24 1.30E+06 1.4224325 0 5.26298 26 0 11.104 27 0 11.5807 28 0 10.058 29 0 8.06103 301.30E+06 6.21137 31 0 8.76659 32 0 13.6187 33 0 13.3709 34 0 11.334 35 08.97998 36 1.30E+06 6.88576 37 0 9.27495 38 0 14.0147 39 0 13.6908 40 011.6019 41 0 9.21185 42 0 7.09208 43 0 5.40321 44 0 4.1331 45 0 3.2099146 0 2.55212 47 0 2.08796 48 1.30E+06 1.76074 49 0 5.58776 50 0 11.415851 0 11.88 52 0 10.3453 53 0 8.33688 54 1.30E+06 6.47618 55 0 9.02081 560 13.8627 57 0 13.6052 58 0 11.5589 59 0 9.1959 60 1.30E+06 7.09304 61 09.47395 62 0 14.2057 63 0 13.8742 64 0 11.778 65 0 9.38036 66 0 7.2543367 0 5.55898 68 0 4.28264 69 0 3.35346 70 0 2.68993 71 0 2.22026 721.30E+06 1.88775 73 0 5.70968 74 0 11.5329 75 0 11.9924 76 0 10.4532 770 8.44044 78 1.30E+06 6.57559 79 0 9.11625 80 0 13.9543 81 0 13.6931 820 11.6434 83 0 9.27696 84 1.30E+06 7.17086 85 0 9.54865 86 0 14.2775 870 13.943 88 0 11.8441 89 0 9.44431 90 0 7.31525 91 0 5.61745 92 04.33877 93 0 3.40735 94 0 2.74167 95 0 2.26992 96 1.30E+06 1.93543 97 05.75546 98 0 11.5768 99 0 12.0346 100 0 10.4937 101 0 8.47931 1021.30E+06 6.61292 103 0 9.15208 104 0 13.9887 105 0 13.7261 106 0 11.6751107 0 9.30739 108 1.30E+06 7.20008 109 0 9.5767 110 0 14.3044 111 013.9689 112 0 11.8689 113 0 9.46813 114 0 7.33811 115 0 5.63941 116 04.35985 117 0 3.42759 118 0 2.76109 119 0 2.28857 120 0 1.95333

Concentration-time profiles are presented over 120 hours for themodified release formulation in Table 14 and are depicted in FIG. 2. A 1g formulation administered TID is also depicted for comparison purposes.

TABLE 14 Cmax, Cmin and Cavg for 1.3 g TID (8:00 AM, 2:00 PM, and 10:00PM) Simulation at 120 hours Pharmacokinetic Parameter Conc. Cmax 12.0,14.0, 14.3 mcg/mL Cmin 1.9, 6.6, 7.2 mcg/mL Cavg 8.4 mcg/mL

Example 6

In Example 6, a study of a single dose followed by multiple doses, wasperformed on 20 healthy non-smoking adult female volunteers using amodified release formulation prepared in accordance with Example 1.After an overnight fast, subjects received a single oral dose oftranexamic acid (1.3 g) on Day 1. Blood samples were taken before dosingand up to 36 hours post-dose. Subjects received another single oral doseof tranexamic acid (1.3 g) on the evening of Day 2, and 3 times a day(every 8 hours) starting on the morning of Day 3 until the last dose onthe morning of Day 7. Blood samples were taken before the 6th, 9th, 12thand 15th dose (the last dose) for the determination of C_(min), and upto 8 hours after the last dose, for the determination of drugconcentration at steady-state. Subjects were housed from at least 10hours before the 1st dose on Day 1 until after the 8-hour blood drawfollowing the 15th dose (on Day 7).

Tranexamic acid is minimally bound (approximately 3%) to plasma proteins(mainly plasminogen) at “typical” therapeutic plasma concentrations ofapproximately 5-15 mg/L. The main route of elimination of tranexamicacid is renal glomerular filtration. After oral administration oftranexamic acid (250 or 500 mg) to healthy adults, between 40-70% of theadministered dose is excreted unchanged in the urine within 24 hours.After IV administration (1 g) 30% of the dose is excreted unchanged inthe urine within one hour, 45-55% within 2-3 hours and 90% within 24hours.

The beta elimination half-life of tranexamic acid is 2 hours. Based onpublished data, the mean C_(max) and AUC₀₋₆ pharmacokinetic parametersafter a single 1.3 g oral dose of tranexamic acid are expected to beapproximately 65% of those achieved with a 2 g dose (i.e. ˜10 mg/L and˜40 mg-h/L, C_(max) and AUC₀₋₆ under fasting conditions, respectively).

However, the pharmacokinetics of tranexamic acid were not adequatelycharacterized in Pilbrant, et al., Eur. J. Clin. Pharmacol,(1981)-20:65-72, since blood samples were collected for up to only 6hours post-dose. In addition, the plasma concentration-time curves afterIV administration showed three exponential phases, with a gammaelimination half-life of approximately 7 hours. For this reason, theconcentration-time profile of tranexamic acid was estimated bysimulating the data over 36 hours, after oral administration of a 1.3 gdose under fasting conditions, using NONMEM. Based on the simulationresults, it would be appropriate to collect blood samples until 36 hoursin order to characterize the AUC, Cmax, tmax, t½ and F.

The objective of this study of Example 6 was to assess thepharmacokinetic linearity of the test tablet formulation of tranexamicacid (modified release), after a single oral dose (Day 1) compared to adaily (1.3 g every 8 hours) dosage regimen (Days 2 to 7), under fastingconditions.

In the study of Example 6, blood samples (1×5 mL) were collected inblood collection tubes containing lithium heparin at Hour 0 (pre-dose)on Day 1, and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 14, 24,28, 32, and 36 hours post-dose. Blood samples for Cmin determinationswere also collected immediately before the 6th, 9th, 12th, and 15thdoses on Days 4, 5, 6, and 7, respectively, and at the following timesafter the 15th dose: 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, and 8 hours.Plasma samples were separated by centrifugation, then frozen at −20°C.±10° C. and kept frozen until assayed at AAI Development Services inNew-Ulm, Germany.

Noncompartmental Pharmacokinetic Parameters

Calculations for plasma tranexamic acid were calculated bynoncompartmental methods using the following pharmacokinetic parametersin Tables 15 and 16:

Day 1:

TABLE 15 AUC 0-t: The area under the plasma concentration versus timecurve, from time 0 to the last measurable concentration, as calculatedby the linear trapezoidal method. AUCinf: The area under the plasmaconcentration versus time curve from time 0 to infinity. AUCinf wascalculated as the sum of AUC 0-t plus the ratio of the last measurableplasma concentration to the elimination rate constant. AUC/AUCinf: Theratio of AUC 0-t to AUCinf. Cmax: Maximum measured plasma concentrationover the time span specified. tmax: Time of the maximum measured plasmaconcentration. If the maximum value occured at more than one time point,tmax was defined as the first time point with this value. kel: Apparentfirst-order terminal elimination rate constant calculated from asemi-log plot of the plasma concentration versus time curve. Thisparameter was calculated by linear least squares regression analysisusing the maximum number of points in the terminal log- linear phase(e.g. three or more non-zero plasma concentrations). t½: The apparentfirst-order terminal elimination half-life was calculated as 0.693/kel.

No value for kel, AUCinf or t½ were reported for cases that did notexhibit a terminal log-linear phase in the concentration versus timeprofile.

Day 7:

TABLE 16 AUCτ: The area under the plasma concentration versus time curveover the final dosing interval, as calculated by the linear trapezoidalmethod. Cmax: Maximum measured plasma concentration over the finaldosing interval. Cmin: Measured plasma concentration prior to themorning dose. tmax: Time of the maximum measured plasma concentrationover the final dosing interval. If the maximum value occured at morethan one time point, tmax was defined as the first time point with thisvalue. Flux: Percent fluctuation was calculated as follows: Flux 1: Cmax− Cmin × 100 Cssav where Cssav was calculated as the ratio of AUC 0-τ tothe dosing interval, τ. Flux 2: Cmax − Cmin × 100 Cmin

Compartmental Pharmacokinetic Parameters

Compartmental analysis was performed on tranexamic acid data followingsingle and multiple oral administrations of the modified release (MR)tablet formulation. Multiple compartmental models were constructed andtheir ability to fit plasma concentrations of tranexamic acid wereevaluated using a standard two-stage (STS) approach with ADAPT-II(maximum likelihood analysis). The discrimination process was performedby computing the Akaike Information Criterion Test (AIC), the minimumvalue of the objective function (OBJ) and by looking at pertinentgraphical representations of goodness of fit (e.g. fitted and observedconcentrations versus time).

The final analysis was performed using an iterative two-stage approachwith the IT2S® software. This software uses a population methodologywhich allows one to provide robust PK parameter estimates on anindividual subject and population basis. All relevant pharmacokineticparameters were calculated and reported. Concentrations were modeledusing a weighting procedure of W_(j)=1/S_(j) ² where the variance σj²was calculated for each observation using the equation σj²=(a+b*Y_(j))²where a and b are the intercept and slope of each variance model. Theslope is the residual variability associated with each concentration(includes the intra-individual variability and the sum of allexperimental errors), and the intercept is related to the limit ofdetection of the analytical assay. All PK parameter estimates wereupdated iteratively during the population PK analysis (VARUP, IT2S®)until stable values were found. The analysis included the quantitativeestimation of population PK parameters and interindividual variabilityof tranexamic acid in plasma.

Individual profiles of observed vs fitted plasma concentrations oftranexamic acid were provided for the MR formulation.

Statistical Analyses Descriptive Statistics

Descriptive statistics including arithmetic means, standard deviationsand coefficients of variation were calculated on the individualconcentration and pharmacokinetic data. Additionally, geometric meanswere calculated for the parameters AUC_(0-t), AUC_(inf), and C_(max) forDay 1 and AUCτ, C_(max) and C_(min) for Day 7.

Time Dependence Pharmacokinetic Linearity

The pharmacokinetic parameter AUCτ (Day 7) was compared againstAUC_(inf) (Day 1) using an analysis of variance (ANOVA) on theln-transformed values for tranexamic acid. The ANOVA model includedGroup, Day (1 (AUC_(inf)) and 7 (AUCτ)) and the interaction Day*Group asfixed effects. All the interaction terms were not statisticallysignificant, at a level of 5%, and were dropped from the final model.The ANOVA included calculation of least-squares means (LSM), thedifference between Day LSM and the standard error associated with thisdifference. The above statistical analysis was done using the SAS® GLMprocedure.

The ratio of LSM was calculated using the exponentiation of the Day LSMfrom the analysis on the ln-transformed response. The ratio wasexpressed as a percentage relative to AUC_(inf) (Day 1).

A ninety percent confidence interval for the ratio was derived byexponentiation of the confidence interval obtained for the differencebetween Day LSM resulting from the analysis on the ln-transformedresponse. The confidence interval was expressed as a percentage relativeto AUC_(inf) (Day 1).

Steady-State Analysis

A steady-state analysis was performed, on the ln-transformed pre-doseCmin concentrations at −72, −48, −24 and 0-hour time points, usingHelmert's contrasts. The ANOVA model included Group, Time and theinteraction Time*Group as fixed effects. In order to model thecorrelations within every subject, an appropriate variance-covariancematrix was chosen among the following: unstructured (UN), compoundsymmetry (CS), compound symmetry heterogeneous (CSH), variance component(VC), autoregressive (AR(1)), autoregressive heterogeneous (ARH(1)) andautoregressive moving average (ARMA(1,1)), using the Akaike's Burnhamand Anderson criterion (AICC). All the interaction terms were notstatistically significant, at a level of 5%, and were dropped from thefinal model. The ANOVA included also calculation of least-squares means(LSM) for each pre-dose C_(min) concentrations. Helmert's contrasts wereconstructed such that each time point is compared to the mean ofsubsequent time points. There are 3 contrasts associated to the 4pre-dose concentration timepoints. They are listed in Table 17 below:

TABLE 17 Contrast Tests Compar. 1 Predose Day 4 compared to (meanpredose of Day 5, 6 and 7) Compar. 2 Predose Day 5 compared to (meanpredose of Day 6 and 7) Compar. 3 Predose Day 6 compared to predose Day7 (0-hour)

The above statistical analyses were done using the SAS® Mixed procedure.

Formula

The following formulae in Table 18 were used for the ratio ofleast-squares means and 90% confidence interval calculations derivedfrom the ANOVA on the ln transformed pharmacokinetic parameters.

TABLE 18 Ratio of Least-squares 100 × e^((LSM) ^(Day7) ^(−LSM) ^(Day1) ⁾Means: 90% Confidence Interval: 100 × e^((LSM) ^(Day7) ^(−LSM) ^(Day1)^(±t) ^(df,0.05) ^(×SE) ^(Day7−Day1) ⁾ Note: LSM_(Day7) and LSM_(Day1)are the least-squares means of Day 7 and Day 1, as computed by theLSMEANS statement of the SAS ® GLM procedure. t_(df,α) is the value ofthe Student's t distribution with df degrees of freedom (i.e. degrees offreedom for the error term from the analysis of variance) and aright-tail fractional area of α (α = 0.05). SE_(Day7−Day1) is thestandard error of the difference between the adjusted Day means, ascomputed by the ESTIMATE statement in the SAS ® GLM procedure.

Discussion of Pharmacokinetic Results Time Dependence PharmacokineticLinearity

The ANOVA model included Group, Day (1 (AUC_(inf)) and 7 (AUCτ)) and theinteraction Day*Group as the fixed effect. All the interaction termswere not statistically significant, at a level of 5%, and were droppedfrom the final model. Pharmacokinetic linearity was calculated for theformulation using the same approach as above, but the ANOVA modelincluded Group, Day 1 (AUCinf) and Day 7 (AUC′)) and the interactionsGroup*Day as fixed effects and Subject nested within Group as a randomeffect.

The pharmacokinetic linearity results are summarized in the table below.

Table 19

TABLE 19 Ratio 90% Confidence Interval Formulation AUCτ/AUCinf LowerLimit Upper Limit MR 97.3 86.5 109.5

The pharmacokinetic linearity results indicate that the ratios ofleast-squares means of AUCτ (Day 7) to AUC_(inf) (Day 1) and the 90%confidence interval for the MR formulation were within the 80-125%acceptance range. Based on these results, the 650 mg tranexamic acidmodified release tablets exhibited linear pharmacokinetics followingrepeated administration (7 days) of a 1.3 g dose under fastingconditions.

Steady-State Analysis

For the steady-state analysis, the CS variance-covariance matrix waschosen to model the correlations within every subject. Overall, theinteraction term (i.e. Time*Group) was not statistically significant andwas removed from the final ANOVA model. For each formulation, the sameapproach as above was used, but the ANOVA models included Group, Timeand the interactions Time*Group as fixed effects.

A summary of LSM results for the steady-state analysis are summarized inTable 20A below.

TABLE 20A Times Formulation Days (hour) LSM derived from the ANOVA MR 4−72 4.90536 5 −48 4.77323 6 −24 5.23678 7 0 5.15389

Summary of statistical comparisons for the steady-state analysis aresummarized in Table 20B below

TABLE 20B Formulation Helmert's contrasts P-value MR Predose Day 4compared to (mean predose of 0.4438 Day 5, 6 and 7) Predose Day 5compared to (mean predose of 0.0393 Day 6 and 7) Predose Day 6 comparedto predose Day 7 0.7318

Based on the results above, steady-state plasma concentration oftranexamic acid were reached on Day 4 (−72-hour), since the p value forthe first contrast was not statistically significant at a 5% alphaerror. It should be noted that the second comparison [Predose Day 5compared to (mean of Day 6 and 7)] was found to be statisticallysignificant.

The largest difference observed in predose plasma concentrations oftranexamic acid between the LSM of predose Day 5 compared to Day 6 and 7was less than 10%, which is not considered clinically relevant.Moreover, the last contrast was not statistically significant and theobserved difference between the LSM of predose Day 6 and 7 was less than2%.

Compartmental Pharmacokinetic Analysis

The mean apparent oral clearance (CL/F) of the MR formulation calculatedwith compartmental methods was 17.7 L/h (295 mL/min). Based on previousdata reported in the literature, the group of Pilbrant, et al., havedetermined that the urinary recovery of tranexamic acid exceeded 95% ofthe dose administered. Considering the bioavailability of the MRformulation (Mean F: 44.9%, See Table 5), the systemic clearance (CL) oftranexamic acid (295 mL/min×0.449=123 mL/min) would be close to theglomerular filtration rate in healthy subjects (125 mL/min)5.

Using compartmental methods, the mean T½γ for the MR formulation was16.6 hours. Similar values of terminal elimination half-life werepreviously reported in the literature. Pilbrant A., et al., Eur. J.Clin. Pharmacol (1981), 20: 65-72.

Following a single oral dose of 1.3 g of the MR formulation, the meanplasma concentrations of tranexamic acid observed at 28, 32, and 36hours were 0.19724, 0.15672, and 0.13624 mcg/mL, respectively.Considering the therapeutic window of tranexamic acid (5-15 mcg/mL) andthe very low plasma concentration levels observed at these timepoints,the terminal elimination half-life (T½γ) characterizing the slow declineof plasma concentrations should not play a clinically significant rolein the frequency of drug administration.

Pharmacokinetic Conclusions

The pharmacokinetic linearity results indicate that the ratios ofleast-squares means of AUCτ (Day 7) to AUCinf (Day 1) and the 90%confidence interval for the MR formulation were within the 80-125%acceptance range. Based on these results, the 650 mg tranexamic acidmodified release tablets exhibited linear pharmacokinetics followingrepeated administration (7 days) of a 1.3 g dose under fastingconditions.

Steady-state plasma concentrations of tranexamic acid for themodified-release tablets were reached on Day 4 (−72-hour), since thep-value for the first contrast was not statistically significant at a 5%alpha error

The pharmacokinetics of tranexamic acid was properly described using athree compartment PK model with linear elimination. The absorptionkinetic of the single-dose (Day 1) data of tranexamic acid for the MRformulation was best described using a mixed-order rate constant ofabsorption.

Plasma Pharmacokinetic Parameters for the modified release (MR)formulation of Tranexamic Acid on day 1 are listed in Table 21 below.

TABLE 21 ln ln AUC_(0-t)* AUC_(inf)* ln Half- (mcg · (mcg · C_(max)*T_(max) life K_(el) h/ml) h/ml) (mcg/ml) (h) (h) (1/h) Mean 74.57176.875 13.176041 3.079 11.078 0.06443 CV % 31.3 30.4 33.1 25.0 16.9 18.3N 19 19 19 19 19 19 *For ln-transformed parameters, the antilog of themean (i.e. the geometric mean) is reported; AUC_(0-t) = AUC post dose(0-36 hours)

Plasma Pharmacokinetic Parameters for the modified release (MR)formulation of Tranexamic Acid on day 7 are listed in Table 22 below.

TABLE 22 ln AUC_(τ)* ln C_(max)* ln C_(min)* T_(max) Flux 1** Flux 2**(mcg · h/ml) (mcg/mL) (mcg/ml) (h) (%) (%) Mean 74.791 15.8035095.157681 2.553 113.16 219.21 CV % 29.0 30.1 31.2 14.4 21.6 44.6 N 19 1919 19 19 19 *For ln-transformed parameters, the antilog of the mean(i.e. the geometric mean) is reported; AUC_(τ) = AUC dosing interval (8hours) **Defined in Table 16

Menorrhagia Instrument

In clinical trials the primary goal is to obtain definitive evidenceregarding the benefit to risk profile of the pharmacotherapy. One of themost challenging design tasks in studies of heavy menstrual bleedingwhich is a subjective complaint is the choice of efficacy endpoints oroutcome measures. The Applicants have established two criteria forassessing the clinical relevance of the reduction in menstrual bloodloss in the clinical efficacy studies. The first criterion was that themean reduction in menstrual blood loss should be greater than 50 mL. Thesecond criterion was based on the correlation between the reduction inmenstrual blood loss and the subjects' perception of a meaningfulsymptomatic change, derived from blinded data from the measures of theMenorrhagia Instrument (MI) in the first treated menstrual period in themenstrual cycle during a controlled clinical study for safety andefficacy of tranexamic acid in heavy menstrual Bleeding. Analysis of thedata for the symptomatic measures of the Menorrhagia Instrument (MI,measure six, FIG. 7) established that a menstrual blood loss reductionof at least 36 mL as defined by the alkaline hematin test was regardedas meaningful by the clinical patients. The mean reduction in menstrualblood loss in patients treated with a tranexamic acid formulation at 1.9and at 3.9 g/day met both criteria for a clinically meaningful result.Data from Menorrhagia Instrument (MI, measure six, FIG. 1, whichestablishes that the treatment was meaningful to the patient providesthe treating practitioner with an assessment of patient response totranexamic acid therapy.

Example 7 Mennoraghia Impact Measure Validation

Objective measurements of menstrual blood loss are not practical in thehealthcare setting, and they correlate poorly with a woman's subjectiveassessment of blood loss and its simpact on quality of life [Warner2004; National Collaborating Centre for Women's and Children's Health,2007]. Menorrhagia is a subjective condition and may be practicallydefined as menstrual loss that is greater than the woman feels that shecan reasonably manage. The amelioration of symptoms of heavy menstrualloss are practical efficacy benefits of the treatment are thereforeimportant to measure and validate in a controlled clinical environment.

The MI was evaluated in a sub population of patients enrolled in aclinical trial designed to assess the safety and efficacy of modifiedrelease tranexamic acid formulations (Example 1) at an oral dose of 3.9g administered daily for up to 5 days during each menstrual period. Twogroups of patients were used to assess the MI, one group of patientswere those diagnosed with menorrhagia and undergoing treatment. Thesecond group was an age matched normal group. The sub-study wasdesigned: to collect sufficient quantitative data to support theconstruct-related validation of the MI measures; to collect sufficientquantitative data to support the assessment of meaningful/importantchange in blood loss to the women; to conduct a test/retest evaluationof the instrument, and to address the reliability of the MI measures.

Study Methods

Development of the MI began with a review of the literature focusing onthe methods used to collect qualitative data from menorrhagia patients.Qualitative interviews with patients determined which symptomaticconcepts were most important to women and could be included in a draftImpact Measure. Cognitive debriefing interviews to evaluate patientunderstanding of items led to the synthesis of a patient-basedinstrument for assessing the impact of limitations caused by heavymenstrual bleeding. Published measures were used in the evaluation ofthe psychometric properties of the Menorrhagia Instrument to assessConstruct-Related Validity. The reference measures include, the RutaMenorrhagia Questionnaire [Ruta 1995] and the Medical Outcomes StudyShort-Form 36 Item Health Status Instrument (SF-36) [Ware 1992]. Scoringof the standardized measures followed published algorithms, Table 23.

TABLE 23 Descriptions of Instruments used in this study Measure ScoreGenerated Score Ranges Menorrhagia Impact Blood Loss Severity (Q1) 1(light) thru 4 (very heavy) Measure (MI) Limitation Work outside orinside the home 1 (not at all) thru 5 (extremely) (Q2) Physicalactivities (Q3) 1 (not at all) thru 5 (extremely) Social or leisureactivities (Q4) 1 (not at all) thru 5 (extremely) Activity list (Q5)[Descriptive] Change in blood loss (follow-up) (Q6, [15-pt scale: 0 = nochange, 6a, 6b) 1-7 improve, 1-7 worse] Meaningful/important change(Q6c) Y/N Ruta Menorrhagia Global 0 (asymptomatic) - 42 (severe)Questionnaire Specific Physical Function: Impact on work 0(asymptomatic) - 6 (severe) and daily activities (Q9 and Q10) SocialFunction: Impact on social and 0 (asymptomatic) - 8 (severe) leisureactivities and sex-life (Q11 and Q12) SF-36 Physical Functioning,Role-Physical, 0-100 Bodily Pain (100 = minimal impairment) GeneralHealth (can be combined to form Physical Health Component Score);Vitality, Social Functioning, Role- Emotional, Mental Health (can becombined to form Mental Health Component Score)

Study Design

A total of 262 women completed the MI. The MI measures 1 through 5 wereadministered after subject's baseline period and after the subsequentfirst, second, third and sixth treatment periods. The MI measure 6 wasadministered after the first treatment period only. For this validationstudy, only the data collected through Month 1 of treatment was includedin the analyses for the treatment cohort. The MI measures 1-5 wereadministered at baseline and at the subsequent first and secondnon-treatment periods for the subjects in the normal cohort The MImeasure 6 was administered and data collected, at Month 1 and Month 2.The Ruta Menorrhagia Questionnaire, SF-36 Health Survey and the MIQ werecompleted by the subject before visit procedures were performed. Asubset of at least 50 subjects were asked to return to the study site 7to 10 days after the baseline Visit but before the next menstrual periodstarts to complete the MI a second time.

Treatment Group

A total of 177 patients were enrolled into the sub-study. During thistime period 28 patients withdrew consent, dropped-out, or did notproperly complete MI and were non-evaluable. The 149 patients remainingwere intended to be age matched. The majority of patients in the studywere in their late 30's or early 40's. Because of the difficulty ofenrolling sufficient numbers of women with normal menstrual periods inthis age bracket 18 evaluable patients were not age matched. A total of131 evaluable patients were age matched. A sub-set of 80 evaluablepatients participated in the test/retest segment of the validation. Ofthese patients 11 were evaluable but not age matched. Data from all 80patients were used for statistical evaluation of the test/re-testcorrelations.

Normal Group

A group of women with self reported normal menstrual bleeding comprisedthe pool of normal women eligible for age matching in the study. Anormal was defined as all of the following: a menstrual cycle between 26and 32 days long, and their last (most recently completed) menstrualperiod was seven days or less in duration, the heaviest bleeding wasthree days or less, and the woman classified the bleeding overall as“light” or “moderate” as opposed to “heavy” or “very heavy. Women withnormal periods who were enrolled into the study served as age-matchcontrols for women recruited into the treatment group. Un-matching andre-matching occurred throughout the enrollment period if participants ineither group dropped out of the study, if better re-matching increasedthe total number of matched pairs, or if the age-matched woman withnormal periods did not enroll in the study.

Five women enrolled in the study did not complete the study throughVisit 3. Another five women who did complete the study became‘unmatched’ as the Treatment Group participant they had been matched tobecame non-evaluable. The 131 women who completed the study and remainedmatched are the Validation Sample Normal Group. A total of 51 womencompleted the Retest.

The following Measures were summarized and statistically analyzed:

-   -   MI measure1—Blood Loss Rating    -   MI measure 2—Limitation of Work Outside or Inside the Home    -   MI measure 3—Limitation of Physical Activities    -   MI measure 4—Limitation of Social or Leisure Activities    -   MI measure 6/6a/6b—Menstrual Blood Loss During Last Period    -   MI measure 6c—Meaningfulness of Change in Menstrual Blood Loss

The statistics include the counts (missing data), mean, standarddeviation, median, inter-quartile range, and minimum/maximum values.Differences in these variables between the treatment and normal cohortswere assessed using analysis of variance.

A p-value <0.05 was required for significance using two-sided hypothesistests; no p-value adjustments were made for the analysis of multipleendpoints. All analyses were performed under SPSS version 11.5 forWindows, and the Stuart-Maxwell test for homogeneity was performed usingStata version 9.0 for Windows.

Validation of the MI was conducted using standardized analyticprocedures found in the FDA Draft Guidance on Patient Reported Outcomesfor Use in Evaluating Medical Products for Labeling Claims andinstrument review criteria developed by the Scientific AdvisoryCommittee of the Medical Outcomes Trust.¹ 1Scientific Advisory Committeeof the Medical Outcomes Trust. Assessing health status andquality-of-life instruments: attributes and review criteria. Qual LifeRes. 2002; 11: 193-205

Evaluation of the Menorrhagia Instrument

The MI consisted of 4 individual measures (1-4) that were analyzedseparately for validation. No summative scale was derived. Measure 5,served as descriptive of variables and did not undergo standardvalidation analyses. Measures 6, 6a and 6b dealt with menstrual bloodloss relative to the previous menstrual period. The answers to themeasures in the subparts of measure 6, were combined to produce a 15point rating scale. The scale values range from −7 to +7 with −7representing a very great deal worse menstrual blood loss than theprevious period, and +7 representing a very great deal better menstrualblood loss than the previous period. The midpoint (0) represents theperception of about the same menstrual blood loss as the previousperiod.

Test-retest reliability assessed if items produced stable, reliablescores under similar conditions (Guttman, 1945). Reproducibility wasevaluated in a subset of at least 50 from the treatment group and atleast 50 from the normal group 7 to 10 days after the baseline visitusing the intra-class correlation coefficient (ICC, see formula below).Values above 0.70 indicated the stability of an instrument over time.The following formula was used to compute the Intraclass CorrelationCoefficient (ICC):

${ICC} = \frac{A^{2} + B^{2} + C^{2}}{A^{2} + B^{2} + D^{2} + ( \frac{C^{2}}{n} )}$$\begin{matrix}{{where}\text{:}} & {A = {{Standard}\mspace{14mu} {deviation}\mspace{14mu} {of}\mspace{14mu} {baseline}\mspace{14mu} {score}}} \\\; & {B = {{Standard}\mspace{14mu} {deviation}\mspace{14mu} {of}\mspace{14mu} {Time}\mspace{14mu} 2\mspace{14mu} {score}}} \\\; & {C = {{Standard}\mspace{14mu} {deviation}\mspace{14mu} {of}\mspace{14mu} {change}\mspace{14mu} {in}\mspace{14mu} {score}}} \\\; & {D = {{mean}\mspace{14mu} {of}\mspace{14mu} {change}\mspace{14mu} {in}\mspace{14mu} {score}}} \\\; & {n = {{number}\mspace{14mu} {of}\mspace{14mu} {respondents}}}\end{matrix}$

The data for each of the measures was above 0.70. In the testpopulation, n=88, values of 0.72 (0.60-0.81), 0.75 (0.64-0.83), 0.77(0.67-0.84) and 0.76 (0.66-0.84) for measures 1 to 4 respectively. Theaged matched normal values where n=51 were 0.77 (0.63-0.86), 0.67(0.49-0.80), 0.75 (0.60-0.85) and 0.86 (0.77-0.92) respectively.

Construct-Related Validity was established when relationships amongitems, domains, and concepts conform to what was predicted by theconceptual framework for the instrument. This includes convergent,discriminant, and known-groups validity. Convergent and discriminantvalidity was present where measures of the same construct are morehighly related and measures of different constructs were less related.To assess convergent and discriminant validity, Pearson's correlationcoefficients were computed between each MI measure and items and scalesfrom the SF-36 and the Ruta Menorrhagia Questionnaire included in thestudy design and administered at the same visit. The followinghypotheses were tested:

The MI Blood Loss Measure (#1) will have a stronger association with theRuta Menorrhagia Questionnaire (RMQ) than to the SF-36 subscales.

The MI Physical Activity Limitation Measure (#3) will have a strongerassociation with the RMQ Physical Function scale, the SF-36 Physicaldomain, the SF-36 Role-Physical domain, and SF-36 Physical ComponentSummary score than the Ruta Social, SF-36 Social, and SF-36 Vitalitydomains.

The MI Social/Leisure Activity Limitation will have a have strongerassociations with the RMQ Social Function scale and the SF-36 SocialFunction domain than the RMQ Physical, the SF-36 Physical and SF-36Bodily Pain domains.

For convergent validity, the correlations of MI measures with Rutasubscales, SF-36 subscales, and diary data are shown in Table 24. TheRuta global score was highly correlated with each MI measures (range0.757-0.809). The correlations of items with the SF-36 subscales werelow to moderate, which is to be expected since the SF-36 is not adisease-specific measure, but rather a more generic health statusmeasure unable to detect differences between a normal population and apopulation of women with menorrhagia. The MI measures were more stronglycorrelated with the SF-36 Physical and Role Physical subscales thanother SF-36 subscales.

TABLE 24 Correlations Between Menorrhagia Insrtument Patient ReportedOutcome (PRO) Measures and Ruta/SF-36/Diary MI measure 2 MI Limit workMI measure 3 MI measure 4 measure 1 outside Limit physical Limit socialor Blood Loss or inside home activity leisure activity Ruta - 0.767  0.785 (0.000)   0.807 (0.000)   0.809 (0.000) Global (0.000)   Ruta -0.512   0.682 (0.000)   0.646 (0.000)   0.664 (0.000) Physical (0.000)Fx Ruta - 0.606   0.634 (0.000)   0.659 (0.000)   0.683 (0.000) Social(0.000) Fx SF-36 - −0.229 −0.234 (0.000) −0.264 (0.000) −0.273 (0.000)Physical (0.000) Fx SF-36 - −0.118 −0.194 (0.002) −0.200 (0.001) −0.261(0.000) Social (0.057) Fx SF-36 - −0.200 −0.279 (0.000) −0.258 (0.000)−0.303 (0.000) Role (0.001) Physical SF-36 - −0.143 −0.193 (0.002)−0.248 (0.000) −0.250 (0.000) Vitality (0.021) SF-36 - −0.087 −0.168(0.006) −0.192 (0.002) −0.205 (0.001) Bodily (0.163) Pain SF-36 - −0.190−0.271 (0.000) −0.285 (0.000) −0.275 (0.000) PCS (0.002)

The data supported the hypothesis that the MI Blood Loss measure (#1)had a stronger association with the Ruta global score than to the SF-36subscales. While the hypothesis that MI measure #3 (Physical ActivityLimitation) would be strongly associated to the physical domains of theRMQ (r=0.65) and SF-36 (r=−0.26) was confirmed, this measure was alsostrongly correlated to the RMQ Social Functioning (r=0.66). MI measure#4 (Social or Leisure Activity Limitation) was highly correlated to theRMQ Social (r=0.68) and moderately associated with the SF-36 SocialFunctioning domain.

Known-groups validity determined the ability of the instrument todiscriminate between groups of subjects known to be distinct. Theability of the MI items to discriminate among known groups was assessedby comparing the 4 items (1 thru 4) to responses from the two groups(treatment and normal) at baseline. Differences in these variables,between the treatment and normal groups, were assessed using analysis ofvariance. A p-value <0.05 was required for significance using two-sidedhypothesis tests; no p-value adjustments was made for the analysis ofmultiple endpoints.

For each MI measure, the mean score for the treatment group wassignificantly different than the mean score for the normal group(p<0.001). The treatment group scores were higher for each individualmeasure, indicating greater limitation as a result of their excessivemenstrual blood loss (see Table 25).

TABLE 25 Known-Groups Validity of the MIQ AGE MATCH Treatment NORMALCohort Cohort St. St. N Mean Dev. N Mean Dev. F (sig.)¹ MISelf-perceived 131 3.25 0.61 131 2.10 0.61 234.727 measure 1 blood loss(<0.001) MI Limit you in your 131 3.04 0.99 131 1.34 0.59 286.864measure 2 work (<0.001) MI Limit you in your 131 3.28 0.95 131 1.49 0.72299.011 measure 3 physical activities (<0.001) MI Limit you in your 1313.05 1.06 131 1.37 0.72 227.312 measure 4 social/leisure (<0.001)activities

The ability to detect change required that values for the item orinstrument change when the concept it measures changed. In order tomeasure the MI items ability to detect change, longitudinal data wereevaluated focusing primarily on the changes from baseline to month 1.Differences in proportions and comparisons between treatment and normalgroups were compared using chi-square statistics (the Stuart-Maxwelltest testing marginal homogeneity for all categories simultaneously).Cohen Effect Size statistics were also compared between the treatmentand normal groups. The Cohen Effect Size was computed by taking the meanchange in measure score (baseline to month 1) and dividing that by thestandard deviation of mean baseline score². 2 Cohen, J. J. (1988).Statistical power analysis for the behavioral sciences (p. 8). Erlbaum:Hillsdale, N.J.

Ability to detect change was described for each item in Tables 26A-D byindicating the distribution of baseline and month 1 response optionpairs for all patients. Change in responses from baseline to month 1 wastested using the Stuart-Maxwell test. For the treatment group, there wassignificant change in responses to each measure from baseline to monthone (p<0.001). For the normal group, none of the items had significantchanges in responses from baseline to month one. FIG. 8 illustrates thedistribution of responses to measure 1 at baseline and at month one. Inthe treatment group, the proportion reporting light or moderate bleedingas measured with item 1, increased from baseline to month 1, and in thenormal group this proportion changed very little.

TABLE 26A Sensitivity to change of the MI Measure 1 Month 1 Stuart-Response Very Maxwell test Cohort category Light Moderate Heavy Heavy ofassociation Treatment Baseline Light 0 0 0 0 59.09 (0.0%) (0.0%) (0.0%)(0.0%) (p < 0.001) Moderate 0 8 4 0 (0.0%) (6.3%) (3.2%) (0.0%) Heavy 341 24 2 (2.4%) (32.5%) (19.0%) (1.6%) Very 2 18 13 11 Heavy (1.6%)(14.3%) (10.3%) (8.7%) Normal Baseline Light 9 5 0 0  6.35 (6.9%) (3.8%)(0.0%) (0.0%) (p = 0.130) Moderate 12 77 4 0 (9.2%) (59.2%) (3.1%)(0.0%) Heavy 0 9 8 2 (0.0%) (6.9%) (6.2%) (1.5%) Very 0 2 2 0 Heavy(0.0%) (1.5%) (1.5%) (0.0%)

TABLE 26B Sensitivity to change of the MI Measure 2 Month 1 Stuart-Response Not at Quite Maxwell test Cohort category all SlightlyModerately a bit Extremely of association Treatment Baseline Not at all5 0 1 1 0 53.33 (4.0%) (0.0%) (0.8%) (0.8%) (0.0%) (p < 0.001) Slightly12 11 2 1 0 (9.5%) (8.7%) (1.6%) (0.8%) (0.0%) Moderately 17 26 14 1 0(13.5%) (20.6%) (11.1%) (0.8%) (0.0%) Quite a bit 2 8 5 9 0 (1.6%)(6.3%) (4.0%) (7.1%) (0.0%) Extremely 3 3 3 1 1 (2.4%) (2.4%) (2.4%)(0.8%) (0.8%) Normal Baseline Not at all 89 5 1 0 0  2.86 (69.0%) (3.9%)(0.8%) (0.0%) (0.0%) (p = 0.517) Slightly 8 13 4 2 0 (6.2%) (10.1%)(3.1%) (1.6%) (0.0%) Moderately 0 3 4 0 0 (0.0%) (2.3%) (3.1%) (0.0%)(0.0%) Quite a bit 0 0 0 0 0 (0.0%) (0.0%) (0.0%) (0.0%) (0.0%)Extremely 0 0 0 0 0 (0.0%) (0.0%) (0.0%) (0.0%) (0.0%)

TABLE 26C Sensitivity to change of the MI Measure 3 Month 1 Stuart-Response Not at Quite Maxwell test Cohort category all SlightlyModerately a bit Extremely of association Treatment Baseline Not at all0 0 1 0 0 64.58 (0.0%) (0.0%) (0.8%) (0.0%) (0.0%) (p < 0.001) Slightly12 12 1 1 0 (9.5%) (9.5%) (0.8%) (0.8%) (0.0%) Moderately 14 20 11 3 0(11.1%) (15.9%) (8.7%) (2.4%) (0.0%) Quite a bit 6 17 9 5 0 (4.8%)(13.5%) (7.1%) (4.0%) (0.0%) Extremely 5 2 2 3 2 (4.0%) (1.6%) (1.6%)(2.4%) (1.6%) Normal Baseline Not at all 72 9 0 0 0  1.99 (55.4%) (6.9%)(0.0%) (0.0%) (0.0%) (p = 0.708) Slightly 14 18 3 1 0 (10.8%) (13.8%)(2.3%) (0.8%) (0.0%) Moderately 0 6 4 1 0 (0.0%) (4.6%) (3.1%) (0.8%)(0.0%) Quite a bit 0 1 1 0 0 (0.0%) (0.8%) (0.8%) (0.0%) (0.0%)Extremely 0 0 0 0 0 (0.0%) (0.0%) (0.0%) (0.0%) (0.0%)

TABLE 26D Sensitivity to change of the MI Measure 4 Month 1 Stuart-Response Not at Quite Maxwell test Cohort category all SlightlyModerately a bit Extremely of association Treatment Baseline Not at all6 3 0 0 0 60.77 (4.8%) (2.4%) (0.0%) (0.0%) (0.0%) (p < 0.001) Slightly16 10 0 2 0 (12.7%) (7.9%) (0.0%) (1.6%) (0.0%) Moderately 19 14 12 2 1(15.1%) (11.1%) (9.5%) (1.6%) (0.8%) Quite a bit 5 14 4 6 0 (4.0%)(11.1%) (3.2%) (4.8%) (0.0%) Extremely 3 4 1 3 1 (2.4%) (3.2%) (0.8%)(2.4%) (0.8%) Normal Baseline Not at all 84 11 0 0 0  1.71 (64.6%)(8.5%) (0.0%) (0.0%) (0.0%) (p = 0.807) Slightly 10 14 2 0 0 (7.7%)(10.8%) (1.5%) (0.0%) (0.0%) Moderately 0 4 2 0 0 (0.0%) (3.1%) (1.5%)(0.0%) (0.0%) Quite a bit 0 0 0 2 0 (0.0%) (0.0%) (0.0%) (1.5%) (0.0%)Extremely 1 0 0 0 0 (0.8%) (0.0%) (0.0%) (0.0%) (0.0%)

The amount of change in each item from baseline to month 1 is shown inTable 27. For the treatment group, the mean change in response frombaseline to month 1 ranged from −0.76 to −1.16 for the four items. Thecalculated effect size shows this amount of change for each item rangedfrom −0.9 to −1.2. For the normal group, the mean change in responsefrom baseline to month 1 ranged from 0.03 to −0.12 for the four items.The effect size for each item ranged from 0.053 to −0.197. This analysisshows a large response in patients undergoing treatment and little to noresponse in normal women who have received no treatment. This instrumentis capable of identifying the perceived improvement in menstrual bloodloss.

TABLE 27 Sensitivity to Change of MI Effect Size BASELINE MONTH 1 CHANGESt St St Effect Menorrhagia Item n Mean Dev n Mean Dev n Mean Dev Size¹Item Self-perceived 126 3.25 0.62 126 2.49 0.73 126 −0.76 0.84 −1.226 1blood loss Item Limit you in your 126 3.05 0.99 126 2.12 0.99 126 −0.931.13 −0.939 2 work Item Limit you in your 126 3.29 0.95 126 2.13 1.00126 −1.16 1.17 −1.221 3 physical activities Item Limit you in your 1263.06 1.06 126 2.00 1.04 126 −1.06 1.19 −1.000 4 social/leisureactivities BASELINE St CHANGE St Effect Menorrhagia Item n Mean Dev nMean n Mean Dev Size Item Self-perceived 130 2.10 0.61 130 1.98 130−0.12 0.56 −0.197 1 blood loss Item Limit you in your 129 1.32 0.57 1291.35 129 0.03 0.50 0.053 2 work Item Limit you in your 130 1.49 0.72 1301.43 130 −0.06 0.57 −0.083 3 physical activities Item Limit you in your130 1.37 0.72 130 1.33 130 −0.04 0.58 −0.056 4 social/leisure activities

Responses from treatment group participants were divided based on twoseparate responder definitions. In the first definition, a responder wasa patient indicating a one-category change in MI measure 1. In thesecond definition, a responder was a patient who entered the study as“Very heavy” or “Heavy” (MI measure 1) and then, following treatment(month 1), indicated being “Moderate” or “Light”. When the treatmentgroup was analyzed using the first responder definition, 69 (90%) of the77 responders reported improvement and 63 (91%) of these rated thisimprovement as “a meaningful change”. Thirty-five (71%) of the 49non-responders reported improvement and 35 (92%) rated their change as“a meaningful change”.

When the treatment group was analyzed using the second responderdefinition, 57 (89%) of the 64 responders reported improvement, and 52(91%) reported their change to be meaningful. Forty-seven (76%) of the62 non-responders reported improvement, and 45 (90%) reported theirchange to be meaningful. Among the normal group, 96 (73%) of 130patients reported no change. Twenty-one (16%) reported improvement, and13 (10%) reported worsening. Of the patients reporting change, 15 (44%)rated the change as “a meaningful change”.

For those women on treatment who reported a meaningful improvement(78.6%), MI items 3 and 4 showed the greatest treatment effect withimprovements of 1.29 and 1.17, respectively. As expected, the majorityof the Normal cohort (73.3%) reported no change in their menstrualperiod.

Example 8

The following clinical study was carried out in order to evaluate theefficacy and safety of tranexamic acid provided as an oral modifiedrelease formulation of Example 1 to reduce menstrual blood loss (MBL) inwomen with menorrhagia when administered during menstruation compared toplacebo.

This was a multi-center, double-blind, placebo-controlled,parallel-group study. The study consisted of a screening phase of two(2) menstrual periods (no treatment) to determine eligibility, followedby a treatment phase spanning three (3) menstrual periods to assess theefficacy and safety of tranexamic acid during menstruation.

The primary objective of the study was to determine the efficacy of a1.95 gm/day of tranexamic acid (650 mg orally three times daily, TID)and 3.9 gm/day of tranexamic acid (1.3 gm orally three times daily, TID)administered during menstruation for up to 5 days (maximum of 15 doses)to reduce menstrual blood loss in women with objective evidence of heavymenstrual bleeding.

The secondary objective of the study was to determine the improvementwith administration of 1.95 gm/day or 3.9 gm/day of tranexamic acid inwomen with heavy menstrual bleeding in their symptoms including,Limitation in Social Leisure Activities (LSLA) and Limitation inPhysical Activities (LPA) scores from the Menorrhagia InstrumentMeasures (FIG. 7). Further the objective was to determine the safety ofthe 1.95 gm/day and 3.9 gm/day of the modified release tranexamic acidformulation administered during menstruation.

Three treatment periods were averaged for the menstrual blood loss (MBL)primary efficacy evaluation (first, second, and third periods ontreatment). All periods were evaluated for the secondary endpoints, andfor safety of tranexamic acid at an oral dose of 1.3 gm or placeboadministered three (3) times daily for up to five consecutive (5) days(maximum of 15 doses) during menstruation.

Criteria for Evaluation Safety and Efficacy Assessments EfficacyAssessment

Menstrual blood loss (MBL) was assessed during the entire menstrualperiod by the alkaline hematin test (AHT) method. The MenorrhagiaInstrument Measures (FIG. 7) were also administered immediately aftereach menstrual period under investigation. For the Primary Endpoint, theobjective reduction in menstrual blood loss (MBL) during the entiremenstrual period as assessed by the AHT Method was assessed.

For the Secondary Endpoints, the scores for Limitation in Social LeisureActivities (LSLA) and the scores for Limitation in Physical Activities(LPA) from the Menorrhagia Instrument Measures (MI), measures #4 and #3,respectively) were assessed.

For the Secondary Endpoints the data collected included at least;Menstrual Blood Loss (MBL) assessment score (MI measure 1), Limitationin Work Outside or Inside the Home (LWH) score (MI item 2), and subjectassessment of meaningfulness score from the MI (measure 6) (used for theMBL responder analysis).

Efficacy Results

The efficacy results were based on the modified ITT (mITT) populations.Results from the analysis of other populations were very similar tothose derived from the analysis of the mITT population, and do not alterthe general conclusions presented below. The numbers of subjects in themITT populations in the efficacy study are summarized in Table 28 below:

TABLE 28 Numbers of Subjects in mITT Populations in Pivotal EfficacyStudies Treatment N Placebo 67 Tranexamic acid (1.95 g/day) 115Tranexamic acid (3.9 g/day) 112

Primary Efficacy Endpoint

Subjects in both treatment groups experienced a significant reductionfrom baseline in mean MBL The mean reduction in MBL in subjects treatedwith the higher dose (3.9 g/day) was 65.3 mL, or 38.6% compared with thebaseline value (p<0.0001). A smaller reduction was observed in subjectsat the lower dose of 1.95 g/day (46.5 mL, 26.1%, p<0.0001). Thereductions in both groups were statistically significant (p<0.0001) whencompared with that in the placebo control group (2.98 mL).

Key Secondary Efficacy Endpoints

Significant treatment-related reductions from baseline in mean LSLAscore and mean LPA score were observed. Other secondary efficacyendpoints provided supportive evidence of the efficacy of tranexamicacid. Specifically, subjects' assessments of MBL (MI item 1) and LWH (MImeasure 2), were both significantly reduced for subjects in the 3.9g/day tranexamic acid group compared with placebo. The number ofpatients responding to treatment was assessed. A responder was definedas a subject with a reduction in MBL and a subjective “meaningful”improvement according to the MI (measure 6c) after the first menstrualcycle during the treatment period. The proportion of responders in thisstudy was 58.3% and 71.0% in the 1.95 and 3.9 g/day tranexamic acidgroups respectively, compared with placebo response rate of 23.4%(p<0.0001 for both dose levels).

These results demonstrate that tranexamic acid at doses of 1.9 and 3.9g/day ameliorates the symptoms associated with HMB, including at leastlimitations in social, leisure, and physical functioning. In addition,these results provide converging evidence that tranexamic acidmodified-release tablets are efficacious in the treatment of HMB.

Heavy Menstrual Bleeding in Patients with Fibroids Included in ClinicalStudy of this Example

Analyses was initiated to assess tranexaminc acid modifdied releasetablets treatment effect stratified by the presence of fibroids atbaseline. The primary goal of this analysis was to evaluatetreatment-by-fibroids effect across variety of endpoints. The results ofthe analysis is found in the following Tables:

TABLE 29.1 Treatment-Induced Changes in MBL (mL) over Three Cycles ofTherapy Stratified by the Presence of Fibroids MITT Population Change inMBL from Percent Change in MBL Baseline MBL (mL) Baseline (mL) fromBaseline (mL) With Without With Without With Without TreatmentStatistics Fibroids Fibroids Fibroids Fibroids Fibroids FibroidsTranexamic N 50 64 49 63 49 63 acid 3.9 Mean(SD) 192 (93) 149 (68) −80(57) −54 (43) −41 (18) −38 (25) Median 172 129 −67 −51 −37 −43Tranexamic N 44 72 44 71 44 71 acid 1.95 Mean(SD) 211 (151) 157 (73) −45(69) −47 (49) −22 (31) −27 (23) Median 157 126 −38 −43 −26 −31 Placebo N24 43 24 43 24 43 Mean(SD) 180 (93) 139 (43)  −5 (66)  −2 (31)  +2 (25) 0 (25) Median 147 128 0 −2 0 −1 NOTE: MEAN values for baseline cyclesand in-treatment cycles are used in these calculations

TABLE 29.2 Treatment-Induced Changes in MBL (mL) over Three Cycles ofTherapy Stratified by the Presence of Fibroids MITT Population Change inMBL from Percent Change in MBL Baseline MBL (mL) Baseline (mL) fromBaseline (mL) With Without With Without With Without TreatmentStatistics Fibroids Fibroids Fibroids Fibroids Fibroids FibroidsTranexamic N 50 64 142 179 142 179 acid 3.9 Mean(SD) 192 (93) 149 (68)−79 (59) −54 (49) −41 (21) −38 (29) Median 172 129 −68 −55 −41 −43Tranexamic N 44 72 125 209 125 209 acid 1.95 Mean(SD)  211 (151) 157(73) −50 (79) −48 (56) −25 (34) −27 (30) Median 157 126 −45 −45 −29 −33Placebo N 24 43 70 124 70 124 Mean(SD) 180 (93) 139 (43)  −1 (74)  −3(42)  +3 (34)  −1 (32) Median 147 128 +3 0 +1 0 NOTE: MEAN baselinevalues are compared to the individual in-treatment cycles

TABLE 29.3 Percent of Subjects Reaching Specified MBL Reduction Targetsover Three Cycles of Therapy Stratified by the Presence of Fibroids MITTPopulation Percent of subjects Percent of subjects Percent of subjectswith >36 mL with >50 mL reaching normal range reduction in MBL reductionin MBL (<=80 mL) With Without With Without With Without TreatmentStatistics Fibroids Fibroids Fibroids Fibroids Fibroids FibroidsTranexamic n/N 45/53 48/67 35/53 37/67 20/53   39/67 acid 3.9 (%)(84.9%) (71.6%) (66.0%) (55.2%) (37.7%)  (58.2%)* Tranexamic n/N 24/4541/73 19/45 30/73 9/45 24/73 acid 1.95 (%) (53.3%) (56.2%) (42.2%)(41.1%) (20.0%) (32.9%) Placebo n/N  1/24  8/45  1/24  5/45 4/24  8/45(%)  (4.2%) (17.8%)  (4.2%) (11.1%) (16.7%) (17.8%) NOTE: MEAN valuesfor baseline cycles and in-treatment cycles are used in thesecalculations

TABLE 29.4 Percent of Subjects Reaching Specified MBL Reduction Targetsfor All Cycles of Therapy Stratified by the Presence of Fibroids MITTPopulation Percent of subjects with >36 Percent of subjects with >50Percent of subjects reaching mL reduction in MBL mL reduction in MBLnormal range (<=80 mL) With Without With Without With Without TreatmentStatistics Fibroids Fibroids Total Fibroids Fibroids Total FibroidsFibroids Total Tranexamic n/N 115/147 129/189 244/336 94/147 105/189  199/336 59/147 106/189  165/336 acid 3.9 (%) (78.2%) (68.3%) (72.6%)(64.0%) (55.6%) (59.2%) (40.1%) (56.1%) (49.1%) Tranexamic n/N  81/132127/213 208/345 65/132 91/213 156/345 37/132 79/213 116/345 acid 1.95(%) (61.4%) (59.6%) (60.3%) (49.2%) (42.7%) (45.2%) (28.0%) (37.1%)(33.6%) Placebo n/N 13/72  29/129  42/201 10/72  21/129  31/201 13/72 26/129  39/201 (%) (18.1%) (22.5%) (20.9%) (13.9%) (16.3%) (15.4%)(18.1%) (20.2%) (19.4%) NOTE: MEAN baseline values are compared to theindividual in-treatment cycles

TABLE 30 Treatment-Induced Changes in MI Q1 over Three Cycles of TherapyStratified by the Presence of Fibroids MITT Population Change in Q1 fromBaseline Q1 Post-Baseline Q1 Baseline With Without With Without WithWithout Treatment Statistics Fibroids Fibroids Fibroids FibroidsFibroids Fibroids Tranexamic N 49 63 49 63 49 63 acid 3.9 Mean(SD) 2.92(0.61) 2.71 (0.63) 2.27 (0.57) 2.19 (0.71) −0.65 (0.70) −0.53 (0.80)Median 3.0 2.5 2.33 2.0 −0.67 −0.5 Tranexamic N 44 71 44 71 44 71 acid1.95 Mean(SD) 2.80 (0.63) 2.82 (0.56) 2.40 (0.67) 2.39 (0.62) −0.39(0.60)   −42 (0.65) Median 3.0 3.0 2.33 2.33 −0.33 −0.5 Placebo N 24 4224 42 24 42 Mean(SD) 2.85 (0.52) 2.79 (0.61) 2.67 (0.54) 2.74 (0.53)−0.18 (0.53) −0.05 (0.84) Median 3.0 3.0 2.67 2.67 +0.25 0.0

TABLE 30.1 Treatment-Induced Changes in MI Q2 over Three Cycles ofTherapy Stratified by the Presence of Fibroids MITT Population Change inQ2 from Baseline Q2 Post-Baseline Q2 Baseline With Without With WithoutWith Without Treatment Statistics Fibroids Fibroids Fibroids FibroidsFibroids Fibroids Tranexamic N 49 63 49 63 49 63 acid 3.9 Mean(SD) 3.15(0.90) 2.99 (1.01) 2.17 (0.94) 2.07 (0.96) −0.99 (0.87) −0.92 (1.08)Median 3.0 3.0 2.0 2.0 −1.0 −0.83 Tranexamic N 44 71 44 71 44 71 acid1.95 Mean(SD) 2.98 (1.05) 2.82 (0.56) 2.38 (0.86) 2.27 (0.94) −0.59(0.80) −0.56 (0.97) Median 3.0 3.0 2.33 2.33 −0.67 −0.67 Placebo N 24 4224 42 24 42 Mean(SD) 2.98 (0.85) 2.69 (0.92) 2.78 (0.84) 2.49 (0.92)−0.19 (0.85) −0.20 (0.76) Median 3.0 2.75 2.67 2.42 0.0 −0.17

TABLE 30.2 Treatment-Induced Changes in MI Q3 over Three Cycles ofTherapy Stratified by the Presence of Fibroids MITT Population Change inQ3 from Baseline Q3 Post-Baseline Q3 Baseline With Without With WithoutWith Without Treatment Statistics Fibroids Fibroids Fibroids FibroidsFibroids Fibroids Tranexamic N 49 63 49 63 49 63 acid 3.9 Mean(SD) 3.17(1.06) 2.98 (1.02) 2.13 (0.93) 2.07 (0.96) −1.05 (0.93) −0.92 (1.10)Median 3.0 3.0 2.0 2.0 −1.0 −0.67 Tranexamic N 44 71 44 71 44 71 acid1.95 Mean(SD) 2.92 (1.09) 3.01 (0.90) 2.36 (0.81) 2.24 (0.97) −0.56(0.80) −0.77 (0.94) Median 3.0 3.0 2.33 2.00 −0.58 −0.83 Placebo N 24 4224 42 24 42 Mean(SD) 3.15 (0.88) 2.86 (0.85) 2.72 (0.90) 2.60 (0.90)−0.42 (0.78) −0.26 (0.81) Median 3.0 3.0 2.67 2.67 −0.42 0.0

TABLE 30.3 Treatment-Induced Changes in MI Q4 over Three Cycles ofTherapy Stratified by the Presence of Fibroids MITT Population Change inQ4 from Baseline Q4 Post-Baseline Q4 Baseline With Without With WithoutWith Without Treatment Statistics Fibroids Fibroids Fibroids FibroidsFibroids Fibroids Tranexamic N 49 63 49 63 49 63 acid 3.9 Mean(SD) 3.08(1.11) 2.93 (1.05) 2.00 (0.92) 1.97 (1.05) −1.08 (1.10) −0.96 (1.13)Median 3.0 3.0 2.0 1.67 −1.0 −0.83 Tranexamic N 44 71 44 71 44 71 acid1.95 Mean(SD) 2.98 (1.05) 2.89 (0.97) 2.28 (0.82) 2.13 (0.94) −0.70(0.83) −0.76 (0.98) Median 3.0 3.0 2.33 2.00 −0.67 −0.83 Placebo N 24 4224 42 24 42 Mean(SD) 3.06 (0.95) 2.73 (0.98) 2.68 (0.83) 2.40 (0.91)−0.38 (0.83) −0.32 (0.86) Median 3.5 2.75 2.67 2.33 −0.33 −0.17

TABLE 30.5 Treatment-Induced Changes in MI Q6A-B at Cycle 1 Stratifiedby the Presence of Fibroids MITT Population Change in Q6A-B fromBaseline With Without Treatment Statistics Fibroids Fibroids TotalTranexamic N 46 59 105 acid 3.9 Mean (SD) 4.1 (2.4) 3.1 (3.5) 3.5 (3.1)Median 5.0 3.0 4.0 Tranexamic N 42 67 109 acid 1.95 Mean (SD) 2.8 (2.4)2.7 (3.2) 2.7 (2.9) Median 3.0 3.0 3.0 Placebo N 24 40 64 Mean (SD) −0.3(3.6)   0.8 (3.8) 0.4 (3.8) Median 0 0 0 NOTE: MI items 6, 6a and 6b arecombined into one scale ranging from −7 to +7. There are very strongreasons for this approach.

Example 9

The following clinical study was carried out in order to evaluate theefficacy and safety of the modified release (MR) oral formulation oftranexamic acid of Example 1 to reduce menstrual blood loss (MBL) inwomen with menorrhagia when administered during menstruation compared toplacebo.

This was a multi-center, double-blind, placebo-controlled,parallel-group study. The study consisted of a screening phase of two(2) menstrual periods (no treatment) to determine eligibility, followedby a treatment phase spanning six (6) menstrual periods to assess theefficacy and safety of tranexamic acid during menstruation.

The primary objective of the study was to determine the efficacy of a3.9 gm/day (1.3 gm orally three times daily, TID) administered duringmenstruation for up to 5 days (maximum of 15 doses) to reduce menstrualblood loss in women with objective evidence of heavy menstrual bleeding.

The secondary objective of the study included an evaluation of theimprovement observed from 3.9 gm/day of the modified release tranexamicacid formulation administered during menstruation in women with heavymenstrual bleeding on Limitation in Social Leisure Activities(LSLA)(item 4) and Limitation in Physical Activities (LPA) (MI measure#3) scores from the Menorrhagia Instruments (FIG. 7). Four treatmentperiods were averaged for the menstrual blood loss (MBL) primaryefficacy evaluation (first, second, third and sixth periods). Allperiods were evaluated for the secondary endpoints, the secondaryendpoints, and for safety of tranexamic acid at an oral dose of 1.3 gmor placebo administered three (3) times daily for up to five consecutive(5) days (maximum of 15 doses) during menstruation.

Criteria for Evaluation

Menstrual blood loss (MBL) was assessed during the entire menstrualperiod by the alkaline hematin test (AHT) method. Measures from theMenorrhagia Instrument (FIG. 7) were also administered immediately aftereach menstrual period under investigation. Subjects reported largestains exceeding the capacity of sanitary protection (and other patientreported outcome [PRO] items) during the menstrual period in dailydiaries.

For the Primary Endpoint, the objective reduction in menstrual bloodloss (MBL) during the entire menstrual period as assessed by the AHTMethod was assessed.

For the Secondary Endpoints, the Limitation in Social Leisure Activities(LSLA) and the Limitation in Physical Activities (LPA) scores from theMenorrhagia Instrument (MI measures #4 and #3, respectively) and thetotal number of large stains responder analysis during the menstrualperiod from subject diaries were assessed.

For the Secondary Endpoints, assessment of the following were included,Menstrual Blood Loss (MBL) assessment score (MI measure #1), Limitationin Work Outside or Inside the Home (LWH) score (MI measure #2), andsubject assessment of meaningfulness score from the MI (Measure #6)(used for the MBL responder analysis).

Efficacy Results

The efficacy results were based on the modified ITT (mITT) populations.The numbers of subjects in the mITT populations in the efficacy studyare summarized in the Table below:

TABLE 31 Numbers of Subjects in mITT Populations in Pivotal EfficacyStudies Treatment N Placebo 72 Tranexamic acid (3.9 g/day) 115

Primary Efficacy Endpoint

Subjects experienced a significant reduction from baseline in mean MBL.The mean reduction in MBL in the tranexamic acid-treated subjects was69.6 mL, or 40.4% compared with the baseline value (p<0.0001). Thereduction in MBL was also statistically significant (p<0.0001) whencompared with that in the placebo control group (12.6 mL, 8.2%).

Secondary Efficacy Endpoints

For the secondary efficacy endpoints, significant treatment-relatedreductions from baseline in mean LSLA score and mean LPA score wereobserved. Subjects' assessments of MBL (MI measure #1) and LWH (MImeasure #2), were both significantly reduced for subjects in the 3.9g/day tranexamic acid group compared with placebo.

The number of patients responding to treatment was assessed as describedin the previous example. A responder was defined as a subject with areduction in MBL and a subjective “meaningful” improvement according tothe MI (measure #6c) after the first menstrual cycle during thetreatment period. The proportion of responders increased in the 3.9g/day tranexamic acid treatment group (65.4%) compared with the placebogroup (31.8%, p<0.0001). These results demonstrate that 3.9 g/daytranexamic acid ameliorates the symptoms associated with HMB, includingimprovement in limitations in social, leisure, and physical functioning.In addition, these results provide converging evidence that tranexamicacid modified-release tablets are efficacious in the treatment of HMB.

In both the Example 8 and Example 9 studies, the reduction in menstrualblood loss (MBL) was evident in the first menstrual period aftercommencing treatment with 3.9 g/day tranexamic acid. The response totreatment was maintained for the duration of the study (three and sixmenstrual cycles in Example 8 and Example 9 respectively; Regressionanalysis in the study of Example VIII confirmed that the response totranexamic acid was durable over the six menstrual cycles (regressionslope of −0.90 mL/cycle, p=0.615).

Summary of Clinical Findings from the Studies of Examples 8 and 9

The efficacy and safety of the tranexamic acid (TXA MR) modified releasetablets in the treatment of HMB was demonstrated in one 3-cycletreatment and one 6-cycle treatment, randomized, double-blind,placebo-controlled study. In these studies, the primary outcome measurewas menstrual blood loss (MBL), measured using a validated menstrualblood loss method. The key secondary outcome measures were based onresponses to items on the Menorrhagia Instrument (MI), a validateddisease-specific patient-reported outcome instrument that measuredLimitations in Social or Leisure activities and Limitations in PhysicalActivities. Large stains (soiling beyond the undergarment) and sanitaryproduct use were also included as secondary outcome measures. In thesestudies, subjects were 18 to 49 years of age with a mean age ofapproximately 40 years and a BMI of approximately 32 kg/m2. On average,subjects had an HMB history of approximately 10 years and 40% hadfibroids as determined by transvaginal ultrasound. About 20% weresmokers and approximately 50% reported using alcohol. Approximately 70%were Caucasian, 25% were Black, and 5% were Asian, Native American,Pacific Islander, or Other. Seven percent (7%) of subjects were ofHispanic origin. In addition, approximately 18% of subjects were takingmultivitamins and 7% of subjects were taking iron supplements.

Three-Cycle Treatment Study

This study compared the effects of two doses of tranexamic acid modifiedrelease tablets (1.95 g and 3.9 g given daily for up to 5 days duringeach menstrual period) versus placebo on MBL over a 3-cycle treatmentduration. A total of 304 patients (117 TXA MR 1.95 g/day, 118 TXA MR 3.9g/day, 69 Placebo) were randomized. MBL was significantly reduced inpatients treated with 3.9 g/day TXA MR compared to placebo (mean 3.9g/day TXA MR=65.31 mL [percent MBL reduction=38.6%]; placebo mean=2.98mL [percent MBL reduction=1.9%]; p<0.0001). This reduction met thecriteria for being a clinicallymeaningful improvement (MBL≧50 mL) and ameaningful improvement to women who participated in the trial (MBL≧36mL). The 1.95 g/day dose did not meet the clinically meaningfulimprovement criteria for efficacy thereby establishing 3.9 g/day TXA MRas the minimally effective dose.

Tranexamic acid modified release tablets also significantly reducedlimitations on social, leisure, and physical activities as measured byquestions on the MI, and sanitary products used in the 3.9 g/day dosegroup compared to placebo (see Table 32). No significant treatmentdifferences were observed in response rates on the number of largestains.

TABLE 32 Secondary Outcomes in 3-Cycle Study Mean (SD) P-value vs.Outcome Measure N Reduction* Placebo Social and Leisure Activities (MI)3.9 gm/day TXA MR 112 1.10 (1.12) <0.0001 Placebo 66 0.34 (0.85)Physical Activities (MI) 3.9 gm/day TXA MR 112 0.97 (1.03) <0.0001Placebo 66 0.32 (0.80) Sanitary Products Used 3.9 gm/day TXA MR 112 6.36(6.80) <0.0001 Placebo 67 2.40 (6.13) Reduction in Large Stains** 3.9gm/day TXA MR 111   71 (64.0) 0.156 Placebo 67   35 (52.2) *Positivemeans reflect a decrease from baseline **The reduction in large stainsis reported as the number (%) of women who were classified as responders(i.e., subjects who experienced a positive change from baseline)

Six-Cycle Treatment Study

This study compared the effects of one dose of TXA MR (3.9 g/day) versusplacebo on MBL over a 6-cycle treatment duration. A total of 196patients (123 TXA MR 3.9 g/day, 73 Placebo) were randomized. Replicatingthe results from the 3-cycle treatment study, MBL was significantlyreduced in patients treated with 3.9 g/day TXA MR compared to placebo(mean 3.9 g/day TXA MR=69.6 mL [percent MBL reduction=40.4%]; placebomean=12.6 mL [percent MBL reduction=8.2%]; p<0.0001). This reduction metthe criterion for being a clinically meaningful improvement (MBL≧50 mL)and a meaningful improvement to women (MBL≧36 mL). Limitations onsocial, leisure, and physical activities were also significantly reducedin the 3.9 g/day TXA MR dose group compared to placebo (see Table 33).No significant treatment differences were observed in sanitary productsused or in response rates on the number of large stains.

TABLE 33 Secondary Outcomes in 6-Cycle Study Mean (SD) P-value vs.Outcome Measure N Reduction* Placebo Social and Leisure Activities (MI)3.9 gm/day TXA MR 115 0.89 (0.85) <0.0001 Placebo 72 0.38 (0.82)Physical Activities (MI) 3.9 gm/day TXA MR 115 0.90 (0.86) <0.0001Placebo 72 0.35 (0.90) Sanitary Products Used 3.9 gm/day TXA MR 115 5.20(6.39) 0.129 Placebo 72 4.03 (5.94) Reduction in Large Stains** 3.9gm/day TXA MR 115   66 (57.4) 0.453 Placebo 72   37 (51.4) *Positivemeans reflect a decrease from baseline **The reduction in large stainsis reported as the number (%) of women who were classified as responders(i.e., subjects who experienced a positive change from baseline)

Example 10 Additional Pharmacokinetics

The pharmacokinetics of the modified release tranexamic acid tablets ofExample 1 were further evaluated. After oral administration peak plasmalevels (C_(max)) occurred at approximately 3 hours (T_(max)). Thesystemic bioavailability of the tablets in women aged 18-49 wasapproximately 45%. The mean C_(max) and the area under the plasmaconcentration curve (AUC) remained unchanged after repeated (1.3 gm TID)oral dosing for 5 days as compared to a single 1.3 gm oral dose.

The C_(max) and AUC after administration of a single 1.3 gm dose oftranexamic modified release tablets increased by 7% and 15% after foodintake compared to fasting conditions, respectively. Therefore, themodified release tranexamic acid tablets can be taken with food.

The pharmacokinetic profile of the modified release tranexamic acidtablets was determined in 39 healthy women following a single 1.3 gmoral dose compared to repeated doses of 1.3 gm TID for 5 days. Theresults are shown in Table 34.

TABLE 34 Parameter 1 day 5 days Dose 1.3 gm 1.3 gm TID^(a) AUC (mcg *h/L) 74.6^(b) 74.8^(c) Coefficient of variation 33% 30% C_(max) (mg/L)13.2 15.8 (5.2^(d)) T_(max) (h) 3.1 2.6 T_(1/2) (h)^(e) 11.1 N/A Note:Values represent geometric means, except Tmax which is the arithmeticmean. ^(a)Dosed every 8 hours (3.9 g/day) ^(b)AUC_(0-t) ^(c)AUC_(t)^(d)C_(min) corresponding steady-state concentration ^(e)Reflectsterminal half-life

CONCLUSION

While the invention herein disclosed has been described by means ofspecific embodiments and applications thereof, numerous modificationsand variations could be made thereto by those skilled in the art withoutdeparting from the spirit and scope of the present invention. Suchmodifications are understood to be within the scope of the appendedclaims.

In the preceding specification, the invention has been described withreference to specific exemplary embodiments and examples thereof. Itwill, however, be evident that various modifications and changes may bemade thereto without departing from the broader spirit and scope of theinvention as set forth in the claims that follow. The specification anddrawings are accordingly to be regarded in an illustrative manner ratherthan a restrictive sense.

What is claimed is:
 1. A modified release oral dosage form comprisingtranexamic acid or pharmaceutically acceptable salt thereof and amodified release material which provides for the modified release of thetranexamic acid or pharmaceutically acceptable salt thereof from thedosage form such that the dosage form is suitable for administration ona two or three times a day basis; said dosage form providing an in-vitrodissolution release rate of the tranexamic acid or pharmaceuticallyacceptable salt thereof, when measured by a USP 27 Apparatus Type IIPaddle Method @ 50 RPM in 900 ml water at 37±0.5° C. of less than about70% by weight tranexamic acid or pharmaceutically acceptable saltthereof released at about 45 minutes and about 100% by weight of saidtranexamic acid or pharmaceutically acceptable salt thereof released byabout 120 minutes.
 2. The modified release oral dosage form of claim I,wherein said dosage form provides an in-vitro dissolution release rateof the tranexamic acid or pharmaceutically acceptable salt thereof, whenmeasured by the USP 27 Apparatus Type II Paddle Method @ 50 RPM in 900ml water at 37±0.5° C. of about 0% to about 40% by weight tranexamicacid or pharmaceutically acceptable salt thereof released at about 15minutes, from about 20% to about 60% by weight tranexamic acid orpharmaceutically acceptable salt thereof released at about 30 minutes,from about 40% to about 65% by weight tranexamic acid orpharmaceutically acceptable salt thereof released at about 45 minutes,from about 50% to about 95% by weight tranexamic acid orpharmaceutically acceptable salt thereof released at about 60 minutes,and not less than about 60% by weight tranexamic acid orpharmaceutically acceptable salt thereof released at about 90 minutes.3. The modified release oral dosage form of claim 1, wherein the dosageform releases about 10% to about 25% by weight tranexamic acid orpharmaceutically acceptable salt thereof every 15 minutes when measuredin vitro utilizing the USP 27 Apparatus Type II Paddle Method @ 50 RPMin 900 ml water at 37±0.5° C.
 4. The modified release oral dosage formof claim I, wherein the dosage form releases about 1% tranexamic acid orpharmaceutically acceptable salt thereof every minute when measuredin-vitro utilizing the USP 27 Apparatus Type II paddle method at 50 RPMin 900 ml water at 37±0.5° C.
 5. The modified release oral dosage formof claim 1 which provides a mean maximum plasma concentration (C_(max))of tranexamic acid of from about 9 to about 14.5 mcg/ml after singledose oral administration of about 1300 mg of tranexamic acid orpharmaceutically acceptable salt thereof included in one or more of saidmodified release oral dosage form to humans.
 6. The modified releaseoral dosage form of claim 1 which provides a mean maximum plasmaconcentration (C_(max)) of tranexamic acid of from about 5 to about 25mcg/ml after steady state oral administration of about 1300 mg oftranexamic acid or pharmaceutically acceptable salt thereof included inone or more of said modified release oral dosage form to humans.
 7. Themodified release oral dosage form of claim 1 which provides a meanmaximum plasma concentration (C_(max)) of tranexamic acid of from about10 to about 20 mcg/ml after steady state oral administration of about1300 mg of tranexamic acid or pharmaceutically acceptable salt thereofincluded in one or more of said modified release oral dosage form tohumans.
 8. The modified release oral dosage form of claim 1 whichprovides mean time to maximum plasma concentration (T_(max)) at fromabout 1.0 to about 5.5 hours after oral administration of one or more ofsaid modified release oral dosage form to humans.
 9. The modifiedrelease oral dosage form of claim 1, wherein the dosage form provides amean transit time of said tranexamic acid of 7.70±0.72 hours when orallyadministered across a patient population.
 10. The modified release oraldosage form of claim 1, wherein the dosage form provides a meanabsorption time of said tranexamic acid of 4.18±0.70 hours when orallyadministered across a patient population.
 11. The modified release oraldosage form of claim I, which provides for the reduction of at least oneside effect selected from the group consisting of headache, nausea,vomiting, diarrhea, constipation, cramping, bloating, and combinationsthereof, as compared to an immediate release oral dosage form containingan equivalent amount of tranexamic acid or pharmaceutically acceptablesalt thereof, when administered across a same or different population ofpatients as said modified release dosage form, and wherein saidimmediate release dosage form releases all of said tranexamic acid orpharmaceutically acceptable salt thereof within about 4S minutes whenmeasured in vitro utilizing the USP 27 Apparatus Type II Paddle Method @50 RPM in 900 ml water at 37±0.5° C.
 12. The modified release oraldosage form of claim 1, which provides a mean transit time of saidtranexamic acid which is at least about 20 minutes longer than theimmediate release formulation when administered across a patientpopulation.
 13. The modified release oral dosage form of claim 1, whichprovides a mean absorption time of said tranexamic acid which is atleast about 20 minutes longer than the immediate release formulationwhen administered across a patient population.
 14. The modified ‘releaseoral dosage form of claim I, wherein said dosage form provides lessheadache, nausea, or combination thereof in comparison to atherapeutically equivalent amount of tranexamic acid or pharmaceuticallyacceptable salt thereof administered intravenously in five minutes orless when administered across a patient population.
 15. The modifiedrelease oral dosage form of claim 1, wherein said tranexamic acid orpharmaceutically acceptable salt thereof is included in said dosage formin an amount of from about 37.5 mg to about 1 gram.
 16. The modifiedrelease oral dosage form of claim 1, wherein said tranexamic acid orpharmaceutically acceptable salt thereof is included in said dosage formin an amount of about 650 mg.
 17. The modified release oral dosage formof claim I, wherein said dosage form is selected from the groupconsisting of one or more tablets, capsules, granules. powders, pellets.dragees, troches, non-pareils, and pills.
 18. The modified release oraldosage form of claim I, wherein said dosage form provides abioavailability of said tranexamic acid of greater than 40% whenadministered to humans.